Fused dihydro-4h-pyrazolo[5,1-c][1,4]oxazinyl compounds and analogs for treating cns disorders

ABSTRACT

Disclosed are compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein Ring B, A 1 , A 2 , R 6 , w and n1 are defined and described herein; compositions thereof; and methods of use thereof. These compounds are useful for treating a variety of neurological and psychiatric disorders, such as those described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 15/041,827, filed Feb. 11, 2016, now allowed, whichclaims the benefit of U.S. Provisional Application No. 62/115,043, filedFeb. 11, 2015. The disclosures of each of these prior applications arehereby incorporated herein by reference in their entirety.

BACKGROUND

Central nervous system disorders affect a wide range of the populationwith differing severity. Neurological and psychiatric disorders includemajor depression, schizophrenia, bipolar disorder, obsessive compulsivedisorder (OCD), panic disorder, and posttraumatic stress disorder(PTSD), among others. These disorders affect a person's thoughts, mood,behavior and social interactions and can significantly impair dailyfunctioning. See, e.g., Diagnostic and Statistical Manual of MentalDisorders, 4^(th) Ed., American Psychiatric Association (2000)(“DSM-IV-TR”); Diagnostic and Statistical Manual of Mental Disorders,5^(th) Ed., American Psychiatric Association (2013) (“DSM-5”).

Bipolar disorder is a serious psychiatric disorder that has a prevalenceof approximately 2% of the population, and affects both genders alike.It is a relapsing-remitting condition characterized by cycling betweenelevated (i.e., manic) and depressed moods, which distinguishes it fromother disorders such as major depressive disorder and schizophrenia.Bipolar I is defined by the occurrence of a full manic episode, althoughmost individuals experience significant depression. Symptoms of maniainclude elevated or irritable mood, hyperactivity, grandiosity,decreased need for sleep, racing thoughts and in some cases, psychosis.The depressive episodes are characterized by anhedonia, sad mood,hopelessness, poor self-esteem, diminished concentration and lethargy.Bipolar II is defined as the occurrence of a major depressive episodeand hypomanic (less severe mania) episode although patients spendconsiderable more time in the depressive state. Other related conditionsinclude cyclothymic disorder.

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked bycharacteristics such as psychotic symptoms, phasic progression anddevelopment, and/or deterioration in social behavior and professionalcapability. Characteristic psychotic symptoms are disorders of thoughtcontent (e.g., multiple, fragmentary, incoherent, implausible or simplydelusional contents, or ideas of persecution) and of mentality (e.g.,loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder.

Schizophrenia is classified into subgroups: the paranoid type,characterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening; thedisorganized type, also named “hebephrenic schizophrenia,” in whichthought disorder and flat affect are present together; the cataconictype, in which prominent psychomotor disturbances are evident, andsymptoms may include catatonic stupor and waxy flexibility; and theundifferentiated type, in which psychotic symptoms are present but thecriteria for paranoid, disorganized, or catatonic types have not beenmet. The symptoms of schizophrenia normally manifest themselves in threebroad categories: positive, negative and cognitive symptoms. Positivesymptoms are those which represent an “excess” of normal experiences,such as hallucinations and delusions. Negative symptoms are those wherethe patient suffers from a lack of normal experiences, such as anhedoniaand lack of social interaction. The cognitive symptoms relate tocognitive impairment in schizophrenics, such as lack of sustainedattention and deficits in decision making.

Neurological and psychiatric disorders can exhibit a variety ofsymptoms, including cognitive impairment, depressive disorders, andanxiety disorders.

Cognitive impairment includes a decline in cognitive functions orcognitive domains, e.g., working memory, attention and vigilance, verballearning and memory, visual learning and memory, reasoning and problemsolving (e.g., executive function, speed of processing and/or socialcognition). In particular, cognitive impairment may indicate deficits inattention, disorganized thinking, slow thinking, difficulty inunderstanding, poor concentration, impairment of problem solving, poormemory, difficulties in expressing thoughts, and/or difficulties inintegrating thoughts, feelings and behavior, or difficulties inextinction of irrelevant thoughts.

Depressive disorders include major depressive disorder and dysthymia,and are associated with depressed mood (sadness), poor concentration,insomnia, fatigue, appetite disturbances, excessive guilt and thoughtsof suicide.

Anxiety disorders are disorders characterized by fear, worry, anduneasiness, usually generalized and unfocused as an overreaction to asituation. Anxiety disorders differ in the situations or types ofobjects that induce fear, anxiety, or avoidance behavior, and theassociated cognitive ideation. Anxiety differs from fear in that anxietyis an emotional response to a perceived future threat while fear isassociated with a perceived or real immediate threat. They also differin the content of the associated thoughts or beliefs.

SUMMARY

While medications exist for some aspects of these diseases, thereremains a need for effective treatments for various neurological andpsychiatric disorders, including mood disorders such as bipolar andrelated disorders, psychosis and schizophrenia. For example, while moodstabilizers such as lithium and valproate, antidepressants andantipsychotic drugs are used to treat mood disorders, more effectivemedications are necessary. And current antipsychotics may be successfulin treating the positive symptoms of schizophrenia but fare less wellfor the negative and cognitive symptoms. Additionally, currentantidepressants are typically effective only for a proportion ofpatients suffering from depression.

In some embodiments, the present invention encompasses the insight thatcompounds of Formula (I):

and pharmaceutically acceptable salts thereof, wherein Ring B, A¹, A²,R⁶, w and n1 are defined and described herein, are useful for treating avariety of neurological and psychiatric disorders, such as thosedescribed herein.

Also provided herein are methods for the treatment of variousneurological and psychiatric disorders using the compounds andcompositions provided herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In some embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:Ring B is a 6-membered aromatic ring, which ring unsubstituted orsubstituted with 1 to 4 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃; or is a 5- or 6-memberedheteroaromatic ring having 1 to 3 ring heteroatoms independentlyselected from O, N and S, which ring is unsubstituted or substitutedwith 1 to 3 substituents independently selected from halo, —OH, —NH₂,—CH₃, —CH₂F, —CHF₂ and —CF₃;A¹ is —H or C₁₋₃ alkyl; andA² is —C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R;or A¹ and A², together with the carbon atom to which they are attached,form

m is 0, 1 or 2;n1 is 1 or 2;n2 is 0 or 1;n3 is 0 or 1;p is 0 or 1;R is —H or C₁-C₃ alkyl; or R is —CH₂—(X), —CH₂CH₂—(X), —CH₂—(Z) or—CH₂CH₂—(Z);each instance of R⁵ independently is halo, —CH₃ or ethyl;each instance of R⁶ independently is halo or —CH₃;R⁷ is —H or C₁-C₃ alkyl;R⁸ is —H or C₁-C₃ alkyl which is unsubstituted or substituted with C₃-C₆cycloalkyl;R⁹ is —H, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; andR¹⁰ is —H or C₁-C₃ alkyl;or R⁹ and R⁸, together with the atoms to which they are attached, form(i.e., R⁹ and R⁸, together with the atoms to which they are attachedform a ring such that—C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰ is)

or R⁹ and R¹⁰, together with the nitrogen atom to which they areattached, form

w is 0, 1 or 2;

X is CH or CH₂; and Z is CH, CH₂ or O. 2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75th Ed.Additionally, general principles of organic chemistry are described inM. Loudon, Organic Chemistry, 5th Ed., Roberts and Company, GreenwoodVillage, Colo.: 2009; and M. B. Smith, March's Advanced OrganicChemistry: Reactions, Mechanisms and Structure, 7th Ed., John Wiley &Sons, Hoboken: 2013, the entire contents of which are herebyincorporated by reference.

As used herein, the term “halogen” or “halo” means F, Cl, Br, or I.

As used herein, the term “alkylene” refers to a bivalent alkyl group. An“alkylene chain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein nis a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3,from 1 to 2, or from 2 to 3. A substituted alkylene chain is apolymethylene group in which one or more methylene hydrogen atoms arereplaced with a substituent. Suitable substituents include thosedescribed herein for a substituted aliphatic group.

As used herein, the terms “heteroaryl” and “heteroar-,” used alone or aspart of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,”refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ringatoms; having 6, 10, or 14 □ electrons shared in a cyclic array; andhaving, in addition to carbon atoms, from one to five ring heteroatoms.Heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, andpteridinyl. A heteroaryl group may be monocyclic or bicyclic. The term“heteroaryl” may be used interchangeably with the terms “heteroarylring,” “heteroaryl group,” or “heteroaromatic,” any of which termsinclude rings that are optionally substituted. The term “heteroaralkyl”refers to an alkyl group substituted by a heteroaryl, wherein the alkyland heteroaryl portions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to ring carbon atoms, one to four ringheteroatoms. When used in reference to a ring atom of a heterocycle, theterm “nitrogen” includes a substituted nitrogen. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur and nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as inN-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals includetetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl,pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein. A heterocyclyl group may be monocyclic orbicyclic. The term “heterocyclylalkyl” refers to an alkyl groupsubstituted by a heterocyclyl, wherein the alkyl and heterocyclylportions independently are optionally substituted.

As used herein, the term “unsaturated,” as used herein, means that amoiety has one or more units of unsaturation.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As used herein, the term “heteroatom” means one or more of oxygen,sulfur, nitrogen, phosphorus, or silicon (including, any oxidized formof nitrogen, sulfur, phosphorus, boron, or silicon; the quaternized formof any basic nitrogen or; a substitutable nitrogen of a heterocyclicring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl) or ⁺NR (as in N-substituted pyrrolidinyl)).

As used herein, the term “aryl” used alone or as part of a larger moietyas in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to carbocyclicaromatic ring systems having a total of six to fourteen ring atoms. Theterm “aryl” may be used interchangeably with the term “aryl ring.”Examples of “aryl” groups include phenyl, naphthyl, anthracyl and thelike, which may be optionally substituted.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺ (C₁₋₄ alkyl)₄ salts. Representative alkalior alkaline earth metal salts include sodium, lithium, potassium,calcium, magnesium, and the like. Further pharmaceutically acceptablesalts include, when appropriate, nontoxic ammonium, quaternary ammonium,and amine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

Unless otherwise specified, the word “includes” (or any variationthereon, e.g., “include”, “including”, etc.) is intended to beopen-ended. For example, “A includes 1, 2 and 3” means that A includesbut is not limited to 1, 2 and 3.

Unless otherwise specified, the phrase “such as” is intended to beopen-ended. For example, “A can be a halogen, such as chlorine orbromine” means that A can be, but is not limited to, chlorine orbromine.

3. Description of Exemplary Embodiments

In some embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:Ring B is a 6-membered aromatic ring, which ring is unsubstituted orsubstituted with 1 to 4 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃; or is a 5- or 6-memberedheteroaromatic ring having 1 to 3 ring heteroatoms independentlyselected from O, N and S, which ring is unsubstituted or substitutedwith 1 to 3 substituents independently selected from halo, —OH, —NH₂,—CH₃, —CH₂F,—CHF₂ and —CF₃;A¹ is —H or C₁₋₃ alkyl; andA² is —C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰;or A¹ and A², together with the carbon atom to which they are attached,form

m is 0, 1 or 2;n1 is 1 or 2;n2 is 0 or 1;n3 is 0 or 1;p is 0 or 1;R is —H or C₁-C₃ alkyl; or R is —CH₂—(X), —CH₂CH₂—(X), —CH₂—(Z) or—CH₂CH₂—(Z);each instance of R⁵ independently is halo, —CH₃ or ethyl;each instance of R⁶ independently is halo or —CH₃;R⁷ is —H or C₁-C₃ alkyl;R⁸ is —H or C₁-C₃ alkyl which is unsubstituted or substituted with C₃-C₆cycloalkyl;R⁹ is —H, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; andR¹⁰ is —H or C₁-C₃ alkyl;or R⁹ and R⁸, together with the atoms to which they are attached, form(i.e., R⁹ and R⁸, together with the atoms to which they are attachedform a ring such that—C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰ is)

or R⁹ and R¹⁰, together with the nitrogen atom to which they areattached, form

w is 0, 1 or 2;

X is CH or CH₂; and Z is CH, CH₂ or O.

Such a compound (including pharmaceutically acceptable salts) isreferred to herein as a “provided compound”. Provided compounds are alsodescribed in U.S. Application No. 62/115,043, filed Feb. 11, 2015, whichis hereby incorporated by reference herein in its entirety.

When R is “—CH₂—(X)” or “—CH₂CH₂—(X)”, this means that the nitrogen atombearing R is attached to the carbon atom represented by X with —CH₂— or—CH₂CH₂—, respectively. For example, when ^(A) and A² together with thecarbon atom to which they are attached, form

(“AA”), if n2 is 1, n3 is 1 and m is 0:

if R is —CH₂—(X), then AA is

and if R is —CH₂CH₂—(X), then AA is

When R is —H or C₁-C₃ alkyl, then X is CH₂.

When R is “—CH₂—(Z)” or “—CH₂CH₂—(Z)”, this means that the nitrogen atombearing R is attached to the carbon atom represented by Z with —CH₂— or—CH₂CH₂—, respectively. For example, when R⁹ and R⁸, together with theatoms to which they are attached, form

(“R98”), if n2 is 1, n3 is 1 and m is 0:

if R is —CH₂—(Z), then R98 is

and if R is —CH₂CH₂—(Z), then R98 is

When R is —H or C₁-C₃ alkyl, then Z is CH₂ or O.

In some embodiments, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:Ring B is a 6-membered aromatic ring, which ring is unsubstituted orsubstituted with 1 to 4 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and—CF₃; or is a 5- or 6-membered heteroaromatic ring having 1 to 3 ringheteroatoms independently selected from O, N and S, which ring isunsubstituted or substituted with 1 to 3 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F,—CHF₂ and —CF₃;A¹ is —H or C₁₋₃ alkyl; andA² is —C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R;or A¹ and A², together with the carbon atom to which they are attached,form

m is 0, 1 or 2;n1 is 1 or 2;n2 is 0 or 1;n3 is 0 or 1;p is 0 or 1;R is —H or C₁-C₃ alkyl; or R is —CH₂—(X), —CH₂CH₂—(X), —CH₂—(Z) or—CH₂CH₂—(Z);each instance of R⁵ independently is halo, —CH₃ or ethyl;each instance of R⁶ independently is halo or —CH₃;R⁷ is —H or C₁-C₃ alkyl;R⁸ is —H or C₁-C₃ alkyl which is unsubstituted or substituted with C₃-C₆cycloalkyl;R⁹ is —H, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; andR¹⁰ is —H or C₁-C₃ alkyl;or R⁹ and R⁸, together with the atoms to which they are attached, form(i.e., R⁹ and R⁸, together with the atoms to which they are attachedform a ring such that—C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰ is)

or R⁹ and R¹⁰, together with the nitrogen atom to which they areattached, form

w is 0, 1 or 2;

X is CH or CH₂; and Z is CH, CH₂ or O.

As defined above, Ring B is a 6-membered aromatic ring, which ring isunsubstituted or substituted with 1 to 4 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃; or is a 5-or 6-membered heteroaromatic ring having 1 to 3 ring heteroatomsindependently selected from O, N and S, which ring is unsubstituted orsubstituted with 1 to 3 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. This description of Ring Bincludes the 2 carbon atoms shared with the pyrazole moiety of Formula(I).

In some embodiments, Ring B is a 6-membered aromatic ring, which ring isunsubstituted or substituted with 1 to 4 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In someembodiments, Ring B is a 6-membered aromatic ring, which ring isunsubstituted or substituted with 1 to 3 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In someembodiments, Ring B is a 6-membered aromatic ring, which ring isunsubstituted or substituted with 1 or 2 substituents independentlyselected from halo, —OH, —NH₂, —CH₃,

—CH₂F, —CHF₂ and —CF₃. In some embodiments, Ring B is a 6-memberedaromatic ring, which ring is unsubstituted or substituted with 1substituent selected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃.In some embodiments, Ring B is an unsubstituted 6-membered aromaticring.

In some embodiments, Ring B is a 5- or 6-membered heteroaromatic ringhaving 1 to 3 ring heteroatoms independently selected from O, N and S,which ring is unsubstituted or substituted with 1 to 3 substituentsindependently selected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and—CF₃. When the resulting compound is stable, a ring N atom can besubstituted with —CH₃.

In some embodiments, Ring B is a 5-membered heteroaromatic ring having 1to 3 ring heteroatoms independently selected from O, N and S, which ringis unsubstituted or substituted with 1 to 3 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In someembodiments, Ring B is a 5-membered heteroaromatic ring having 1 or 2ring heteroatoms independently selected from O, N and S, which ring isunsubstituted or substituted with 1 to 3 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In someembodiments, Ring B is a 5-membered heteroaromatic ring having 1 ringheteroatom selected from O, N and S, which ring is unsubstituted orsubstituted with 1 to 3 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃.

In some embodiments, Ring B is any 5-membered heteroaromatic ringdescribed in the preceding paragraph, which ring is unsubstituted orsubstituted with 1 or 2 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In some embodiments, Ring B isany 5-membered heteroaromatic ring described in the preceding paragraph,which ring is unsubstituted or substituted with 1 substituent selectedfrom halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In some embodiments,Ring B is any 5-membered heteroaromatic ring described in the precedingparagraph, which ring is unsubstituted.

In some embodiments, Ring B is a 6-membered heteroaromatic ring having 1to 3 ring heteroatoms independently selected from O, N and S, which ringis unsubstituted or substituted with 1 to 3 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In someembodiments, Ring B is a 6-membered heteroaromatic ring having 1 or 2ring heteroatoms independently selected from O, N and S, which ring isunsubstituted or substituted with 1 to 3 substituents independentlyselected from halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In someembodiments, Ring B is a 6-membered heteroaromatic ring having 1 ringheteroatom selected from O, N and S, which ring is unsubstituted orsubstituted with 1 to 3 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃.

In some embodiments, Ring B is any 6-membered heteroaromatic ringdescribed in the preceding paragraph, which ring is unsubstituted orsubstituted with 1 or 2 substituents independently selected from halo,—OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In some embodiments, Ring B isany 6-membered heteroaromatic ring described in the preceding paragraph,which ring is unsubstituted or substituted with 1 substituent selectedfrom halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂ and —CF₃. In some embodiments,Ring B is any 6-membered heteroaromatic ring described in the precedingparagraph, which ring is unsubstituted.

As defined above, in some embodiments, A¹ is —H or C₁₋₃ alkyl. In someembodiments, A¹ is —H or —CH₃. In some embodiments, A¹ is —H.

As defined above, n1 is 1 or 2. In some embodiments, n1 is 1. In someembodiments, n1 is 2.

As defined above, w is 0, 1 or 2. In some embodiments, w is 0 or 1. Insome embodiments, w is 0. In some embodiments, w is 1 or 2. In someembodiments, w is 1.

As defined above, each instance of R⁶ independently is halo or —CH₃. Insome embodiments, each instance of R⁶ independently is halo. In someembodiments, each instance of R⁶ independently is —F or —Cl. In someembodiments, each instance of R⁶ is —CH₃.

As defined above, in some embodiments, A² is—C(R′)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰. In some embodiments, p is 0. In someembodiments, R⁷ is —H or —CH₃; and R⁸ is H or unsubstituted C₁-C₃ alkyl.In some embodiments, R⁷ is —H; and R⁸ is H or —CH₃. In some embodiments,R⁹ is —H, C₁-C₃ alkyl, cyclopropyl or cyclobutyl; and R¹⁰ is —H or C₁-C₂alkyl. In some embodiments, R⁹ is —H or C₁-C₃ alkyl; and R¹⁰ is —H or—CH₃. In some embodiments, p is 0; R⁷ is —H or —CH₃; R⁸ is H orunsubstituted C₁-C₃ alkyl; R⁹ is —H, C₁-C₃ alkyl, cyclopropyl orcyclobutyl; and R¹⁰ is —H or C₁-C₂ alkyl. In some embodiments, p is 0;R⁷ is —H; R⁸ is H or —CH₃; R⁹ is —H or C₁-C₃ alkyl; and R¹⁰ is —H or—CH₃. In some embodiments, R⁹ and R¹⁰, together with the nitrogen atomto which they are attached, form

In some embodiments, one of n2 and n3 is 0 and the other is 1. In someembodiments, each of n2 and n3 is 1. In some embodiments, m is 0 or 1.In some embodiments, m is 0. In some embodiments, m is 1 or 2. In someembodiments, m is 1. In some embodiments, R⁵ is halo. In someembodiments, R⁵ is —F or —Cl. In some embodiments, R⁵ is —CH₃ or ethyl.In some embodiments, R⁵ is —CH₃. In some embodiments, Z is CH or CH₂. Insome embodiments, Z is O. In some embodiments, each of n2 and n3 is 1;and Z is O.

As defined above, in some embodiments, A² is—C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰. In some embodiments, p is 0. In someembodiments, R⁷ is —H or —CH₃; and R⁸ is H or unsubstituted C₁-C₃ alkyl.In some embodiments, R⁷ is —H; and R⁸ is H or —CH₃. In some embodiments,R⁹ is —H, C₁-C₃ alkyl, cyclopropyl or cyclobutyl; and R¹⁰ is —H or C₁-C₂alkyl. In some embodiments, R⁹ is —H or C₁-C₃ alkyl; and R¹⁰ is —H or—CH₃. In some embodiments, p is 0; R⁷ is —H or —CH₃; R⁸ is H orunsubstituted C₁-C₃ alkyl; R⁹ is —H, C₁-C₃ alkyl, cyclopropyl orcyclobutyl; and R¹⁰ is —H or C₁-C₂ alkyl. In some embodiments, p is 0;R⁷ is —H; R⁸ is H or —CH₃; R⁹ is —H or C₁-C₃ alkyl; and R¹⁰ is —H or—CH₃. In some embodiments, R⁹ and R¹⁰, together with the nitrogen atomto which they are attached, form

In some embodiments, m is 0 or 1. In some embodiments, m is 0. In someembodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, R⁵ is halo. In some embodiments, R⁵ is —F or —Cl. In someembodiments, R⁵ is —CH₃ or ethyl. In some embodiments, R⁵ is —CH₃.

In some embodiments, R⁹ and R⁸, together with the atoms to which theyare attached, form (i.e., R⁹ and R⁸, together with the atoms to whichthey are attached form a ring such that —C(R⁷)(R⁸)—(CH₂)_(p)—N(R⁹)R¹⁰is)

In some embodiments, each of n2 and n3 is 0. In some embodiments, one ofn2 and n3 is 0 and the other is 1. In some embodiments, each of n2 andn3 is 1. In some embodiments, m is 0 or 1. In some embodiments, m is 0.In some embodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, R⁵ is halo. In some embodiments, R⁵ is —F or —Cl. In someembodiments, R⁵ is —CH₃ or ethyl. In some embodiments, R⁵ is —CH₃. Insome embodiments, R is —H or C₁-C₃ alkyl. In some embodiments, R is —Hor —CH₃. In some embodiments, R is —H. In some embodiments, R is —CH₃.In some embodiments, R is —CH₂—(Z) or —CH₂CH₂—(Z). In some embodiments,R is —CH₂—(Z). In some embodiments, R is —CH₂CH₂—(Z). In someembodiments, Z is CH or CH₂. In some embodiments, Z is O. In someembodiments, each of n2 and n3 is 1; and Z is O.

As defined above, in some embodiments, or A¹ and A², together with thecarbon atom to which they are attached, form

In some embodiments, each of n2 and n3 is 0. In some embodiments, one ofn2 and n3 is 0 and the other is 1. In some embodiments, each of n2 andn3 is 1. In some embodiments, m is 0 or 1. In some embodiments, m is 0.In some embodiments, m is 1 or 2. In some embodiments, m is 1. In someembodiments, R⁵ is halo. In some embodiments, R⁵ is —F or —Cl. In someembodiments, R⁵ is —CH₃ or ethyl. In some embodiments, R⁵ is —CH₃. Insome embodiments, R is —H or C₁-C₃ alkyl. In some embodiments, R is —Hor —CH₃. In some embodiments, R is —H. In some embodiments, R is —CH₃.In some embodiments, R is —CH₂—(X) or —CH₂CH₂—(X). In some embodiments,R is —CH₂—(X).

In some embodiments, a provided compound is a compound of Formula (I-1):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; and R¹,R², R³ and R⁴ are independently —H, halo, —OH, —NH₂, —CH₃, —CH₂F, —CHF₂or —CF₃.

In some embodiments, at least two of R¹, R², R³ and R⁴ are —H. In someembodiments, at least three of R¹, R², R³ and R⁴ are —H. In someembodiments, each of R¹, R², R³ and R⁴ is —H. In some embodiments, R¹,R², R³ and R⁴ are independently —H, halo or —CH₃. In some embodiments,R¹, R², R³ and R⁴ are independently —H, —F or —Cl. In some embodiments,each of R¹, R³ and R⁴ is —H. In some embodiments, each of R¹, R³ and R⁴is —H; and R² is —H, halo or —CH₃. In some embodiments, each of R¹, R³and R⁴ is —H; and R² is H, —F or —Cl. In some embodiments, each of R¹,R² and R⁴ is —H. In some embodiments, each of R¹, R² and R⁴ is —H; andR³ is —H, halo or —CH₃. In some embodiments, each of R¹, R² and R⁴ is—H; and R³ is H, —F or —Cl.

In some embodiments, a provided compound is a compound of Formula(I-1-A):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of R¹, R², R³ and R⁴ is as described in embodiments for Formula(I-1), supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-1-B):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of R¹, R², R³ and R⁴ is as described in embodiments for Formula(I-1), supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula (I-2):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination;Y¹ is N or CR¹′;Y² is N or CR²′;Y³ is N or CR³′; andY⁴ is N or CR⁴′;wherein 1 to 3 of Y¹, Y², Y³ and Y⁴ are N; andR¹′, R²′, R³′ and R⁴′ are independently —H, halo, —OH, —NH₂, —CH₃,—CH₂F, —CHF₂ or —CF₃.

In some embodiments, R¹′, R²′, R³′ and R⁴′ are independently —H, halo or—CH₃. In some embodiments, R¹′, R²′, R³′ and R⁴′ are independently —H,—F or —Cl.

In some embodiments, 2 of Y¹, Y², Y³ and Y⁴ are N. In some embodiments,2 of Y¹, Y², Y³ and Y⁴ are N; and R¹′, R²′, R³′ and R⁴′ areindependently —H, halo or —CH₃. In some embodiments, 2 of Y¹, Y², Y³ andY⁴ are N; and R¹′, R²′, R³′ and R⁴′ are independently —H, —F or —Cl. Insome embodiments, 2 of Y¹, Y², Y³ and Y⁴ are N; and at least 1 of Y¹,Y², Y³ and Y⁴ is CH.

In some embodiments, 1 of Y¹, Y², Y³ and Y⁴ is N. In some embodiments, 1of Y¹, Y², Y³ and Y⁴ is N; and R¹′, R²′, R³′ and R⁴′ are independently—H, halo or —CH₃. In some embodiments, 1 of Y¹, Y², Y³ and Y⁴ is N; andR¹′, R²′, R³′ and R⁴′ are independently —H, —F or —Cl. In someembodiments, 1 of Y¹, Y², Y³ and Y⁴ is N; and at least 2 of Y¹, Y², Y³and Y⁴ are CH. In some embodiments, Y² is N; and R¹′, R³′ and R⁴′ areindependently —H, halo or —CH₃. In some embodiments, Y² is N; and R¹′,R³′ and R⁴′ are independently —H, —F or —Cl. In some embodiments, Y³ isN; and R¹′, R²′ and R⁴′ are independently —H, halo or —CH₃. In someembodiments, Y³ is N; and R¹′, R²′ and R⁴′ are independently —H, —F or—Cl.

In some embodiments, a provided compound is a compound of Formula(I-2-A):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹, Y², Y³ and Y⁴ is as described in embodiments for Formula(I-2), supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-2-B):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹, Y², Y³ and Y⁴ is as described in embodiments for Formula(I-2), supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-2-i):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹, Y² and Y⁴ is as described in embodiments for Formula (I-2),supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula (I-3):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination;Y¹¹ is CR¹″ or a heteroatom selected from O, S, N and NR¹¹;Y¹² is CR²″ or a heteroatom selected from O, S, N and NR¹²; andY¹³ is CR³″ or a heteroatom selected from O, S, N and NR¹³;wherein at least one of Y¹¹, Y¹² and Y¹³ is a heteroatom;R¹″, R²″ and R³″ are independently —H, halo, —OH, —NH₂, —CH₃, —CH₂F,—CHF₂ or —CF₃; and R¹¹, R¹² and R¹³ are independently —H or —CH₃.

In some embodiments, R¹″, R²″ and R³″ are independently —H, halo, or—CH₃. In some embodiments, R¹″, R²″ and R³″ are independently —H, —F or—Cl.

In some embodiments, 2 of Y¹¹, Y¹² and Y¹³ are heteroatoms. In someembodiments, 2 of Y¹¹, Y¹² and Y¹³ are heteroatoms; and R¹″, R²″ and R³″are independently —H, halo, or —CH₃. In some embodiments, 2 of Y¹¹, Y¹²and Y¹³ are heteroatoms; and R¹″, R²″ and R³″ are independently —H, —For —Cl. In some embodiments, 2 of Y¹¹, Y¹² and Y¹³ are heteroatoms; and1 of Y¹¹, Y¹² and Y¹³ is CH.

In some embodiments, 1 of Y¹¹, Y¹² and Y¹³ is a heteroatom. In someembodiments, 1 of Y¹¹, Y¹² and Y¹³ is a heteroatom; and R¹″, R²″ and R³″are independently —H, halo, or —CH₃. In some embodiments, 1 of Y¹¹, Y¹²and Y¹³ is a heteroatom; and R¹″, R²″ and R³″ are independently —H, —For —Cl. In some embodiments, 1 of Y¹¹, Y¹² and Y¹³ is a heteroatom; andat least 1 of Y¹¹, Y¹² and Y¹³ is CH. In some embodiments, Y¹¹ is aheteroatom. In some embodiments, Y¹¹ is a heteroatom; and R²″ and R³″are independently —H, halo, or —CH₃. In some embodiments, Y¹¹ is aheteroatom; and R²″ and R³″ are independently —H, —F or —Cl. In someembodiments, Y¹¹ is a heteroatom; and at least 1 of Y¹² and Y¹³ is CH.

In some embodiments, a provided compound is a compound of Formula(I-3-A):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹¹, Y¹² and Y¹³ is as described in embodiments for Formula(I-3), supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-3-B):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹¹, Y¹² and Y¹³ is as described in embodiments for Formula(I-3), supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-3-i):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹² and Y¹³ is as described in embodiments for Formula (I-3),supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-3-ii):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹² and Y¹³ is as described in embodiments for Formula (I-3),supra, or described in embodiments herein, both singly and incombination.

In some embodiments, a provided compound is a compound of Formula(I-3-iii):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, A²,n1, R⁶ and w is as described in embodiments for Formula (I), supra, ordescribed in embodiments herein, both singly and in combination; andeach of Y¹² and Y¹³ is as described in embodiments for Formula (I-3),supra, or described in embodiments herein, both singly and incombination. In some embodiments, R¹¹ is —H.

In some embodiments, a provided compound is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,A¹, n1, R⁶, R⁷, R⁸, R⁹, R¹⁰ and w is as described in embodiments forFormula (I), supra, or described in embodiments herein, both singly andin combination.

In some embodiments, a provided compound is a compound of Formula(II-1):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, n1,R⁶, R⁷, R⁸, R⁹, R¹⁰ and w is as described in embodiments for Formula(I), supra, or described in embodiments herein, both singly and incombination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, w is 0. In some embodiments, each of R¹ and R⁴ is—H. In some embodiments, w is 0; and each of R¹ and R⁴ is —H. In someembodiments, R⁷ is —H; and R⁸ is —H or —CH₃. In some embodiments, w is0; each of R¹ and R⁴ is —H; R⁷ is —H; and R⁸ is —H or —CH₃. In someembodiments, A¹ is —H or —CH₃. In some embodiments, w is 0; each of R¹and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In someembodiments, w is 0; each of R¹, R² and R⁴ is —H; R⁷ is —H; R⁸ is —H or—CH₃; and A¹ is —H. In some embodiments, w is 0; each of R¹, R² and R⁴is —H; R³ is halo; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In someembodiments, w is 0; each of R¹, R² and R⁴ is —H; R³ is —F or —Cl; R⁷ is—H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, w is 0; each ofR¹, R³ and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In someembodiments, w is 0; each of R¹, R³ and R⁴ is —H; R² is halo; R⁷ is —H;R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, w is 0; each of R¹,R³ and R⁴ is —H; R² is —F or —Cl; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is—H. In some embodiments, w is 0; each of R¹, R², R³ and R⁴ is —H; R⁷ is—H; R⁸ is —H or —CH₃; and A¹ is —H.

In some embodiments, n1 is 1. In some embodiments, n1 is 1; w is 0; eachof R¹, R² and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. Insome embodiments, n1 is 1; w is 0; each of R¹, R² and R⁴ is —H; R³ ishalo; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, n1is 1; w is 0; each of R¹, R² and R⁴ is —H; R³ is —F or —Cl; R⁷ is —H; R⁸is —H or —CH₃; and A¹ is —H. In some embodiments, n1 is 1; w is 0; eachof R¹, R³ and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. Insome embodiments, n1 is 1; w is 0; each of R¹, R³ and R⁴ is —H; R² ishalo; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, n1is 1; w is 0; each of R¹, R³ and R⁴ is —H; R² is —F or —Cl; R⁷ is —H; R⁸is —H or —CH₃; and A¹ is —H. In some embodiments, n1 is 1; w is 0; eachof R¹, R², R³ and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H.

In some embodiments, n1 is 2. In some embodiments, n1 is 2; w is 0; eachof R¹, R² and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. Insome embodiments, n1 is 2; w is 0; each of R¹, R² and R⁴ is —H; R³ ishalo; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, n1is 2; w is 0; each of R¹, R² and R⁴ is —H; R³ is —F or —Cl; R⁷ is —H; R⁸is —H or —CH₃; and A¹ is —H. In some embodiments, n1 is 2; w is 0; eachof R¹, R³ and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. Insome embodiments, n1 is 2; w is 0; each of R¹, R³ and R⁴ is —H; R² ishalo; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, n1is 2; w is 0; each of R¹, R³ and R⁴ is —H; R² is —F or —Cl; R⁷ is —H; R⁸is —H or —CH₃; and A¹ is —H. In some embodiments, n1 is 2; w is 0; eachof R¹, R², R³ and R⁴ is —H; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H.

In some embodiments, R⁹ and R¹⁰, together with the nitrogen atom towhich they are attached, form

In some embodiments, R⁹ and R¹⁰, together with the nitrogen atom towhich they are attached, form

and (a) w is 0; (b) each of R¹ and R⁴ is —H; (c) w is 0; and each of R¹and R⁴ is —H; (d) A¹ is —H or —CH₃; (e) w is 0; each of R¹ and R⁴ is —H;and A¹ is —H; (f) m is 0; (g) w is 0; each of R¹ and R⁴ is —H; A¹ is —H;and m is 0; (h) w is 0; each of R¹, R² and R⁴ is —H; A¹ is —H; and m is0; (i) w is 0; each of R¹, R³ and R⁴ is —H; A¹ is —H; and m is 0; (j) wis 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; and m is 0; (k) one ofn2 and n3 is 0 and the other is 1; (l) w is 0; each of R¹, R², R³ and R⁴is —H; A¹ is —H; m is 0; and one of n2 and n3 is 0 and the other is 1;(m) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is 0; one of n2and n3 is 0 and the other is 1; and Z is CH₂; (n) each of n2 and n3 is1; (o) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is 0; andeach of n2 and n3 is 1; or (p) w is 0; each of R¹, R², R³ and R⁴ is —H;A¹ is —H; m is 0; each of n2 and n3 is 1; and Z is O.

In some embodiments, R⁹ and R¹⁰, together with the nitrogen atom towhich they are attached, form

In some embodiments, R⁹ and R¹⁰, together with the nitrogen atom towhich they are attached, form

and (a) w is 0; (b) each of R¹ and R⁴ is —H; (c) w is 0; and each of R¹and R⁴ is —H; (d) A¹ is —H or —CH₃; (e) w is 0; each of R¹ and R⁴ is —H;and A¹ is —H; (f) m is 0; (g) w is 0; each of R¹ and R⁴ is —H; A¹ is —H;and m is 0; (h) w is 0; each of R¹, R² and R⁴ is —H; A¹ is —H; and m is0; (i) w is 0; each of R¹, R³ and R⁴ is —H; A¹ is —H; and m is 0; or (j)w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; and m is 0.

In some embodiments, a provided compound is a compound of Formula(II-1a):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, n1,R⁶, R⁷, R⁸, R⁹, R¹⁰ and w is as described in embodiments for Formula (I)or (II-1), supra, or described in embodiments herein, both singly and incombination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1) or (II-1), supra, or described inembodiments herein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(II-1b):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, n1,R⁶, R⁷, R⁸, R⁹, R¹⁰ and w is as described in embodiments for Formula (I)or (II-1), supra, or described in embodiments herein, both singly and incombination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1) or (II-1), supra, or described inembodiments herein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(II-2):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, n1,R⁶, R⁷, R⁸, R⁹, R¹⁰ and w is as described in embodiments for Formula(I), supra, or described in embodiments herein, both singly and incombination; and each of Y¹, Y², Y³ and Y⁴ is as described inembodiments for Formula (I-2), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, w is 0. In some embodiments, each of Y¹ and Y⁴ isCH. In some embodiments, w is 0; and each of Y¹ and Y⁴ is CH. In someembodiments, R⁷ is —H; and R⁸ is —H or —CH₃. In some embodiments, w is0; each of Y¹ and Y⁴ is CH; and R⁸ is —H or —CH₃. In some embodiments,A¹ is —H or —CH₃. In some embodiments, w is 0; each of Y¹ and Y⁴ is CH;R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, w is 0;each of Y¹, Y² and Y⁴ is CH; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H.In some embodiments, w is 0; each of Y¹, Y² and Y⁴ is CH; R⁷ is —H; R⁸is —H or —CH₃; A¹ is —H; and n1 is 1.

In some embodiments, a provided compound is a compound of Formula(II-3):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, n1,R⁶, R⁷, R⁸, R⁹, R¹⁰ and w is as described in embodiments for Formula(I), supra, or described in embodiments herein, both singly and incombination; and each of Y¹¹, Y¹² and Y¹³ is as described in embodimentsfor Formula (I-3), supra, or described in embodiments herein, bothsingly and in combination.

In some embodiments, w is 0. In some embodiments, each of Y¹² and Y¹³ isCH. In some embodiments, w is 0; and each of Y¹² and Y¹³ is CH. In someembodiments, R⁷ is —H; and R⁸ is —H or —CH₃. In some embodiments, w is0; each of Y¹² and Y¹³ is CH; and R⁸ is —H or —CH₃. In some embodiments,A¹ is —H or —CH₃. In some embodiments, w is 0; each of Y¹² and Y¹³ isCH; R⁷ is —H; R⁸ is —H or —CH₃; and A¹ is —H. In some embodiments, w is0; each of Y¹² and Y¹³ is CH; R⁷ is —H; R⁸ is —H or —CH₃; A¹ is —H; andn1 is 1.

In some embodiments, a provided compound is a compound of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,A¹, m, n1, n2, n3, R, R⁵, R⁶, w and Z is as described in embodiments forFormula (I), supra, or described in embodiments herein, both singly andin combination.

In some embodiments, a provided compound is a compound of Formula(III-1):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n2, n3, R, R⁵, R⁶, w and Z is as described in embodiments forFormula (I), supra, or described in embodiments herein, both singly andin combination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, (a) w is 0; (b) each of R¹ and R⁴ is —H; (c) w is0; and each of R¹ and R⁴ is —H; (d) A¹ is —H or —CH₃; (e) w is 0; eachof R¹ and R⁴ is —H; and A¹ is —H; (f) m is 0; (g) w is 0; each of R¹ andR⁴ is —H; A¹ is —H; and m is 0; (h) w is 0; each of R¹, R² and R⁴ is —H;A¹ is —H; and m is 0; (i) w is 0; each of R¹, R³ and R⁴ is —H; A¹ is —H;and m is 0; (j) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; and mis 0; (k) R is —H or —CH₃; (l) w is 0; each of R¹, R², R³ and R⁴ is —H;A¹ is —H; m is 0; and R is —H or —CH₃; (m) one of n2 and n3 is 0 and theother is 1; (n) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is0; R is —H or —CH₃; and one of n2 and n3 is 0 and the other is 1; (o) wis 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is 0; R is —H or—CH₃; one of n2 and n3 is 0 and the other is 1; and Z is CH or CH₂; (p)each of n2 and n3 is 1; (q) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹is —H; m is 0; R is —H or —CH₃; and each of n2 and n3 is 1; (r) w is 0;each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is 0; R is —H or —CH₃; eachof n2 and n3 is 1; and Z is CH or CH₂; or (s) w is 0; each of R¹, R², R³and R⁴ is —H; A¹ is —H; m is 0; R is —H or —CH₃; each of n2 and n3 is 1;and Z is O.

In some embodiments, n1 is 1; and (a) w is 0; (b) each of R¹ and R⁴ is—H; (c) w is 0; and each of R¹ and R⁴ is —H; (d) A¹ is —H or —CH₃; (e) wis 0; each of R¹ and R⁴ is —H; and A¹ is —H; (f) m is 0; (g) w is 0;each of R¹ and R⁴ is —H; A¹ is —H; and m is 0; (h) w is 0; each of R¹,R² and R⁴ is —H; A¹ is —H; and m is 0; (i) w is 0; each of R¹, R³ and R⁴is —H; A¹ is —H; and m is 0; (j) w is 0; each of R¹, R², R³ and R⁴ is—H; A¹ is —H; and m is 0; (k) R is —H or —CH₃; (l) w is 0; each of R¹,R², R³ and R⁴ is —H; A¹ is —H; m is 0; and R is —H or —CH₃; (m) one ofn2 and n3 is 0 and the other is 1; (n) w is 0; each of R¹, R², R³ and R⁴is —H; A¹ is —H; m is 0; R is —H or —CH₃; and one of n2 and n3 is 0 andthe other is 1; (o) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; mis 0; R is —H or —CH₃; one of n2 and n3 is 0 and the other is 1; and Zis CH or CH₂; (p) each of n2 and n3 is 1; (q) w is 0; each of R¹, R², R³and R⁴ is —H; A¹ is —H; m is 0; R is —H or —CH₃; and each of n2 and n3is 1; (r) w is 0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is 0; Ris —H or —CH₃; each of n2 and n3 is 1; and Z is CH or CH₂; or (s) w is0; each of R¹, R², R³ and R⁴ is —H; A¹ is —H; m is 0; R is —H or —CH₃;each of n2 and n3 is 1; and Z is O.

In some embodiments, a provided compound is a compound of Formula(III-1a):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n3, R, R⁵, R⁶, w and Z is as described in embodiments for Formula(I) or (III-1), supra, or described in embodiments herein, both singlyand in combination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1) or (III-1), supra, or described inembodiments herein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(III-1b):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n3, R, R⁵, R⁶, w and Z is as described in embodiments for Formula(I) or (III-1), supra, or described in embodiments herein, both singlyand in combination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1) or (III-1), supra, or described inembodiments herein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(III-1c):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n3, R, R⁵, R⁶, w and Z is as described in embodiments for Formula(I) or (III-1), supra, or described in embodiments herein, both singlyand in combination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1) or (III-1), supra, or described inembodiments herein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(III-1d):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n3, R, R⁵, R⁶, w and Z is as described in embodiments for Formula(I) or (III-1), supra, or described in embodiments herein, both singlyand in combination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1) or (III-1), supra, or described inembodiments herein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(III-2):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n2, n3, R, R⁵, R⁶, w and Z is as described in embodiments forFormula (I), supra, or described in embodiments herein, both singly andin combination; and each of Y¹, Y², Y³ and Y⁴ is as described inembodiments for Formula (I-2), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(III-3):

or a pharmaceutically acceptable salt thereof, wherein each of A¹, m,n1, n2, n3, R, R⁵, R⁶, w and Z is as described in embodiments forFormula (I), supra, or described in embodiments herein, both singly andin combination; and each of Y¹¹, Y¹² and Y¹³ is as described inembodiments for Formula (I-3), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein each of Ring B,m, n1, n2, n3, R, R⁵, R⁶, w and X is as described in embodiments forFormula (I), supra, or described in embodiments herein, both singly andin combination.

In some embodiments, a provided compound is a compound of Formula(IV-1):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R⁵, R⁶, w and X is as described in embodiments for Formula(I), supra, or described in embodiments herein, both singly and incombination; and each of R¹, R², R³ and R⁴ is as described inembodiments for Formula (I-1), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, (a) w is 0; (b) each of R¹ and R⁴ is —H; (c) w is0; and each of R¹ and R⁴ is —H; (d) m is 0; (e) w is 0; each of R¹ andR⁴ is —H; and m is 0; (f) w is 0; each of R¹, R² and R⁴ is —H; and m is0; (g) w is 0; each of R¹, R³ and R⁴ is —H; and m is 0; (h) w is 0; eachof R¹, R², R³ and R⁴ is —H; and m is 0; (i) R is —H or —CH₃; (j) w is 0;each of R¹, R², R³ and R⁴ is —H; m is 0; and R is —H or —CH₃; (k) eachof n2 and n3 is 0; (l) w is 0; each of R¹, R², R³ and R⁴ is —H; m is 0;R is —H or —CH₃; and each of n2 and n3 is 0; (m) one of n2 and n3 is 0and the other is 1; (n) w is 0; each of R¹, R², R³ and R⁴ is —H; m is 0;R is —H or —CH₃; and one of n2 and n3 is 0 and the other is 1; (o) eachof n2 and n3 is 1; or (p) w is 0; each of R¹, R², R³ and R⁴ is —H; m is0; R is —H or —CH₃; and each of n2 and n3 is 1.

In some embodiments, n1 is 1; and (a) w is 0; (b) each of R¹ and R⁴ is—H; (c) w is 0; and each of R¹ and R⁴ is —H; (d) m is 0; (e) w is 0;each of R¹ and R⁴ is —H; and m is 0; (f) w is 0; each of R¹, R² and R⁴is —H; and m is 0; (g) w is 0; each of R¹, R³ and R⁴ is —H; and m is 0;(h) w is 0; each of R¹, R², R³ and R⁴ is —H; and m is 0; (i) R is —H or—CH₃; (j) w is 0; each of R¹, R², R³ and R⁴ is —H; m is 0; and R is —Hor —CH₃; (k) each of n2 and n3 is 0; (l) w is 0; each of R¹, R², R³ andR⁴ is —H; m is 0; R is —H or —CH₃; and each of n2 and n3 is 0; (m) oneof n2 and n3 is 0 and the other is 1; (n) w is 0; each of R¹, R², R³ andR⁴ is —H; m is 0; R is —H or —CH₃; and one of n2 and n3 is 0 and theother is 1; (o) each of n2 and n3 is 1; or (p) w is 0; each of R¹, R²,R³ and R⁴ is —H; m is 0; R is —H or —CH₃; and each of n2 and n3 is 1.

In some embodiments, a provided compound is a compound of Formula(IV-2):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R⁵, R⁶, w and X is as described in embodiments for Formula(I), supra, or described in embodiments herein, both singly and incombination; and each of Y¹, Y², Y³ and Y⁴ is as described inembodiments for Formula (I-2), supra, or described in embodimentsherein, both singly and in combination.

In some embodiments, a provided compound is a compound of Formula(IV-3):

or a pharmaceutically acceptable salt thereof, wherein each of m, n1,n2, n3, R, R⁵, R⁶, w and X is as described in embodiments for Formula(I), supra, or described in embodiments herein, both singly and incombination; and each of Y¹¹, Y¹² and Y¹³ is as described in embodimentsfor Formula (I-3), supra, or described in embodiments herein, bothsingly and in combination.

Exemplary compounds of formula (I) are set forth in Table 1, below.

TABLE 1

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

In some embodiments, the present invention provides a compound selectedfrom those depicted in Table 1, above, or a pharmaceutically acceptablesalt thereof. In some embodiments, the pharmaceutically acceptable saltis a hydrochloride salt.

4. Uses, Formulation and Administration and Pharmaceutically AcceptableCompositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention, or a pharmaceuticallyacceptable salt, ester, or salt of ester thereof, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle. In some embodiments, theamount of compound in compositions of this invention is such that iseffective to treat, prevent, and/or manage various neurological and/orpsychiatric disorders and/or symptoms in a patient. In some embodiments,a composition of this invention is formulated for administration to apatient in need of such composition. In some embodiments, a compositionof this invention is formulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an active metabolite or residue thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including capsules,tablets, aqueous suspensions or solutions. In the case of tablets fororal use, carriers commonly used include lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. For oral administration in a capsule form, useful diluentsinclude lactose and dried cornstarch. When aqueous suspensions arerequired for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, provided pharmaceutically acceptable compositionscan be formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon a variety of factors, including the hosttreated and the particular mode of administration. Preferably, providedcompositions should be formulated so that a dosage of between 0.01-100mg/kg body weight/day of a compound of the present invention can beadministered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

5. Uses of Compounds and Pharmaceutically Acceptable Compositions

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating a neurological or psychiatricdisorder.

In some embodiments, the compounds and compositions, according to themethod of the present invention, may be administered using any amountand any route of administration effective for treating a neurologicaland/or psychiatric disorder in a patient.

In some embodiments, the neurological or psychiatric disorder isselected from a psychosis, including schizophrenia (paranoid,disorganized, catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced or drug-induced (phencyclidine, ketamineand other dissociative anesthetics, amphetamine and otherpsychostimulants and cocaine) psychosispsychotic disorder, psychosisassociated with affective disorders, brief reactive psychosis,schizoaffective psychosis, “schizophrenia-spectrum” disorders such asschizoid or schizotypal personality disorders, or illness associatedwith psychosis (such as major depression, manic depressive (bipolar)disorder, Alzheimer's disease and post-traumatic stress syndrome),including both positive, negative, and cognitive symptoms ofschizophrenia and other psychoses; cognitive disorders includingdementia (associated with Alzheimer's disease, ischemia, multi-infarctdementia, trauma, vascular problems or stroke, HIV disease, Parkinson'sdisease, Huntington's disease, Down syndrome, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; anxiety disorders including acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; substance-related disorders andaddictive behaviors (including substance-induced delirium, persistingdementia, persisting amnestic disorder, psychotic disorder or anxietydisorder; tolerance, dependence or withdrawal from substances includingalcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);obesity, bulimia nervosa and compulsive eating disorders; bipolardisorders, mood disorders including depressive disorders; depressionincluding unipolar depression, seasonal depression and post-partumdepression, premenstrual syndrome (PMS) and premenstrual dysphoricdisorder (PDD), mood disorders due to a general medical condition, andsubstance-induced mood disorders; learning disorders, pervasivedevelopmental disorder including autistic disorder, attention disordersincluding attention-deficit hyperactivity disorder (ADHD) and conductdisorder; disorders such as autism, depression, benign forgetfulness,childhood learning disorders and closed head injury; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, Parkinsonism-ALS dementia complex and basal gangliacalcification), medication-induced Parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, muscular spasms anddisorders associated with muscular spasticity or weakness includingtremors; dyskinesias {including drug e.g. L-DOPA induced dyskinesiatremor (such as rest tremor, postural tremor, intention tremor), chorea(such as Sydenham's chorea, Huntington's disease, benign hereditarychorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea andhemiballism), myoclonus (including generalised myoclonus and focalmyoclonus), tics (including simple tics, complex tics and symptomatictics), and dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia)}; urinary incontinence;neuronal damage including ocular damage, retinopathy or maculardegeneration of the eye, tinnitus, hearing impairment and loss, andbrain edema; emesis; and sleep disorders including insomnia andnarcolepsy.

In some embodiments, the neurological or psychiatric disorder isAlzheimer's Disease, Parkinson's Disease, depression, cognitiveimpairment, stroke, schizophrenia, Down Syndrome, or Fetal AlcoholSyndrome. In some embodiments, the neurological or psychiatric disorderis Alzheimer's Disease. In some embodiments, the neurological orpsychiatric disorder is Parkinson's Disease. In some embodiments, theneurological or psychiatric disorder is depression. In some embodiments,the neurological or psychiatric disorder is cognitive impairment. Insome embodiments, the cognitive impairment is cognitive dysfunctionassociated with depression, for example, major depressive disorder. Insome embodiments, the neurological or psychiatric disorder is stroke. Insome embodiments, the neurological or psychiatric disorder isschizophrenia. In some embodiments, the neurological or psychiatricdisorder is Down Syndrome. In some embodiments, the neurological orpsychiatric disorder is Fetal Alcohol Syndrome.

In some embodiments, the neurological or psychiatric disorder involves adeficit in cognition (cognitive domains as defined by the DSM-5 are:complex attention, executive function, learning and memory, language,perceptual-motor, social cognition). In some embodiments, theneurological or psychiatric disorder is associated with a deficit indopamine signaling. In some embodiments, the neurological or psychiatricdisorder is associated with basal ganglia dysfunction. In someembodiments, the neurological or psychiatric disorder is associated withdysregulated locomotor activity. In some embodiments, the neurologicalor psychiatric disorder is associated with impairment of prefrontalcortex functioning.

In some embodiments, the present invention provides a method of treatingone or more symptoms of a neurological and/or psychiatric disorderprovided herein. Such disorders include mood disorders, includingbipolar I disorder, bipolar II disorder, bipolar depression, mania,cyclothymic disorder, substance/medication-induced bipolar and relateddisorders, bipolar and related disorder due to another medicalcondition, other specified bipolar and related disorder, and unspecifiedbipolar and related disorders; psychotic disorders, includingschizophrenia, schizophrenia spectrum disorder, acute schizophrenia,chronic schizophrenia, NOS schizophrenia, schizoid personality disorder,schizotypal personality disorder, delusional disorder, psychosis,psychotic disorder, brief psychotic disorder, shared psychotic disorder,psychotic disorder due to a general medical condition, drug-inducedpsychosis (e.g., cocaine, alcohol, amphetamine), schizoaffectivedisorder, aggression, delirium, Parkinson's psychosis, excitativepsychosis, Tourette's syndrome, and organic or NOS psychosis; depressivedisorders, including disruptive mood dysregulation disorder, majordepressive disorder (MDD) (including major depressive episode),dysthymia, persistent depressive disorder (dysthymia), treatmentresistant depression, premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder dueto another medical condition, other specified depressive disorder, andunspecified depressive disorder; anxiety disorders, including separationanxiety disorder, selective mutism, specific phobia, social anxietydisorder (social phobia), panic disorder, panic attack specifier,agoraphobia, generalized anxiety disorder, substance/medication-inducedanxiety disorder, anxiety disorder due to another medical condition,other specified anxiety disorder, and unspecified anxiety disorder;stressor-related disorders, including reactive attachment disorder,disinhibited social engagement disorder, posttraumatic stress disorder(PTSD), acute stress disorder, and adjustment disorders; and otherdisorders including substance abuse or dependency (e.g., nicotine,alcohol, cocaine), addiction, eating disorders, behavior disorder,seizure, vertigo, epilepsy, agitation, aggression, neurodegenerativedisease, Alzheimer's disease, Parkinson's disease, dyskinesias,Huntington's disease, dementia, premenstrual dysphoria; and attentiondeficit disorder (ADD) and neurodevelopmental disorders, includingattention deficit hyperactivity disorder (ADHD)), autism, autismspectrum disorder, obsessive-compulsive disorder, pain (e.g.,neuropathic pain, sensitization accompanying neuropathic pain, andinflammatory pain), fibromyalgia, migraine, cognitive impairment,movement disorder, restless leg syndrome (RLS), multiple sclerosis,Parkinson's disease, Huntington's disease, dyskinesias multiplesclerosis, sleep disorder, sleep apnea, narcolepsy, excessive daytimesleepiness, jet lag, drowsy side effect of medications, insomnia, sexualdysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson'sdisease, and Huntington's chorea. In some embodiments, the neurologicaland/or psychiatric disorders include agitation and aggression. In someembodiments, the agitation and aggression are associated withAlzheimer's Disease, Parkinson's Disease, and/or autism. In someembodiments, the neurological and/or psychiatric disorders areobsessive-compulsive disorder and related disorders (e.g., bodydysmorphic disorder, hoarding disorder, trichotillomania, excoriationdisorder). In some embodiments, the neurological and/or psychiatricdisorders are disruptive, impulse-control, and conduct disordersincluding oppositional defiant disorder, intermittent explosivedisorder, conduct disorder, antisocial personality disorder, pyromania,kleptomania, other specified disruptive, impulse-control, and conductdisorder, unspecified disruptive, impulse-control, and conduct disorder.

In some embodiments, the present invention provides a method of treatingone or more symptoms including depression (e.g., major depressivedisorder or dysthymia); bipolar disorder, seasonal affective disorder;cognitive deficit; sleep related disorder (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; anxieties(e.g., general anxiety disorder, social anxiety disorder, panicdisorder); obsessive compulsive disorder; post-menopausal vasomotorsymptoms (e.g., hot flashes, night sweats); neurodegenerative disease(e.g., Parkinson's disease, Alzheimer's disease and amyotrophic lateralsclerosis); manic disorder; dysthymic disorder; and obesity.

In some embodiments, a depressive disorder is associated with acutesuicidality or suicide ideation. The United States Food and DrugAdministration has adopted a “black box” label warning indicating thatantidepressants may increase the risk of suicidal thinking and behaviorin some children, adolescents and young adults (up to age 24) with adepressive disorder such as MDD. In some embodiments, a providedcompound does not increase the risk of suicidal thinking and/or behaviorin children, adolescents and/or young adults with a depressive disorder,e.g., with MDD. In some embodiments, the present invention provides amethod of treating one or more symptoms of a depressive disorder (e.g.,MDD) in children, adolescents and/or young adults without increasing therisk of suicidal thinking and/or behavior.

In some embodiments, the present invention provides a method of treatingone or more symptoms including senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome,disturbances of consciousness, coma, lowering of attention, speechdisorder, Lennox syndrome, and hyperkinetic syndrome.

In some embodiments, the present invention provides a method of treatingone or more symptoms of neuropathic pain, including post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

In some embodiments, the present invention provides a method of treatingone or more symptoms including obesity; migraine or migraine headache;and sexual dysfunction, in men or women, including without limitationsexual dysfunction caused by psychological and/or physiological factors,erectile dysfunction, premature ejaculation, vaginal dryness, lack ofsexual excitement, inability to obtain orgasm, and psycho-sexualdysfunction, including without limitation, inhibited sexual desire,inhibited sexual excitement, inhibited female orgasm, inhibited maleorgasm, functional dyspareunia, functional vaginismus, and atypicalpsychosexual dysfunction.

In some embodiments, the present invention provides a method ofsuppressing rapid eye movement (REM) during both sleep and daytimeequivalent.

In some embodiments, the present invention provides a method ofsuppressing or eliminating pathological or excessive REM during thenight or daytime equivalent.

In some embodiments, the present invention provides a method of treatingone or more symptoms including cataplexy (sudden involuntary transientbouts of muscle weakness or paralysis while awake); nighttime sleepdisturbance/sleep fragmentation associated with narcolepsy or otherconditions; sleep paralysis associated with narcolepsy or otherconditions; hypnagogic and hypnapompic hallucinations associated withnarcolepsy or other conditions; and excessive daytime sleepinessassociated with narcolepsy, sleep apnea or shift work disorder and othermedical conditions such as cancer, chronic fatigue syndrome andfibromyalgia.

In some embodiments, the present invention provides a method of treatinga neurological and/or psychiatric disorder described herein, comprisingadministering a compound of the invention in conjunction with one ormore pharmaceutical agents. Suitable pharmaceutical agents that may beused in combination with the compounds of the present invention includeanti-Parkinson's drugs, anti-Alzheimer's drugs, anti-depressants,anti-psychotics, anti-ischemics, CNS depressants, anti-cholinergics, andnootropics. In some embodiments, suitable pharmaceutical agents areanxiolytics.

Suitable anti-Parkinson's drugs include dopamine replacement therapy(e.g. L-DOPA, carbidopa, COMT inhibitors such as entacapone), dopamineagonists (e.g. D1 agonists, D2 agonists, mixed D1/D2 agonists;bromocriptine, pergolide, cabergoline, ropinirole, pramipexole, orapomorphine in combination with domperidone), histamine H2 antagonists,and monoamine oxidase inhibitors such as selegiline and tranylcypromine.

In some embodiments, compounds of the invention can be used incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl(benzhexyl)hydrochloride, COMTinhibitors such as entacapone, MAO A/B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.Lisuride and pramipexole are commonly used in a non-salt form.

Suitable anti-Alzheimer's drugs include beta-secretase inhibitors,gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID'sincluding ibuprofen, vitamin E, and anti-amyloid antibodies. In someembodiments, an anti-Alzheimer's drug is memantine.

Suitable anti-depressants and anti-anxiety agents include norepinephrinereuptake inhibitors (including tertiary amine tricyclics and secondaryamine tricyclics), selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT1A agonists orantagonists, especially 5-HT1A partial agonists, and corticotropinreleasing factor (CRF) antagonists.

Specific suitable anti-depressant and anti-anxiety agents includeamitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, citalopram, escitalopram, maprotiline,nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; desvenlafaxine, duloxetine; aprepitant;bupropion, vilazodone, mirtazapine, lithium, nefazodone, trazodone andviloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate,diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone,flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptablesalts thereof. In some embodiments, suitable anti-depressant andanti-anxiety agents are tianeptine, or pharmaceutically acceptable saltsthereof.

Suitable anti-psychotic and mood stabilizer agents include D2antagonists, 5HT2A antagonists, atypical antipsychotics, lithium, andanticonvulsants.

Specific suitable anti-psychotic and mood stabilizer agents includechlorpromazine, fluphenazine, haloperidol, amisulpride, chlorpromazine,perphenazine, thioridazine, trifluoperazine, aripiprazole, asenapine,clozapine, olanzapine, paliperidone, quetiapine, risperidone,ziprasidone, lurasidone, flupentixol, levomepromazine, pericyazine,perphenazine, pimozide, prochlorperazine, zuclopenthixol, olanzapine andfluoxetine, lithium, carbamazepine, lamotrigine, valproic acid andpharmaceutically acceptable salts thereof.

In some embodiments, compounds of the invention may be used incombination with other therapies. Suitable therapies includepsychotherapy, cognitive behavioral therapy, electroconvulsive therapy,transcranial magnetic stimulation, vagus nerve stimulation, anddeep-brain stimulation.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Insome embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

In some embodiments, a combination of 2 or more therapeutic agents maybe administered together with the compounds of the invention. In someembodiments, a combination of 3 or more therapeutic agents may beadministered with the compounds of the invention.

Other examples of agents the compounds of this invention may also becombined with include: vitamins and nutritional supplements, antiemetics(e.g. 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptorantagonists, histamine receptor antagonists, cannabinoids,benzodiazepines, or anticholinergics), agents for treating MultipleSclerosis (MS) such as beta interferon (e.g., Avonex® and Rebif®),Copaxone®, and mitoxantrone; treatments for asthma such as albuterol andSingulair®; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins, fibrates, cholesterolabsorption inhibitors, bile acid sequestrants, and niacin; agents fortreating liver disease such as corticosteroids, cholestyramine,interferons, and anti-viral agents; agents for treating blood disorderssuch as corticosteroids, anti-leukemic agents, and growth factors;agents for treating immunodeficiency disorders such as gamma globulin;and anti-diabetic agents such as biguanides (metformin, phenformin,buformin), thiazolidinediones (rosiglitazone, pioglitazone,troglitazone), sulfonylureas (tolbutamide, acetohexamide, tolazamide,chlorpropamide, glipizide, glyburide, glimepiride, gliclazide),meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors(miglitol, acarbose), incretin mimetics (exenatide, liraglutide,taspoglutide), gastric inhibitory peptide analogs, DPP-4 inhibitors(vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin),amylin analogs (pramlintide), and insulin and insulin analogs.

In some embodiments, a compound of the present invention, or apharmaceutically acceptable salt thereof, is administered in combinationwith an antisense agent, a monoclonal or polyclonal antibody, or ansiRNA therapeutic.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another, normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of formula I,or a pharmaceutically acceptable salt thereof, an additional therapeuticagent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The amount of both, an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-100 mg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

In some embodiments, the present invention provides a medicamentcomprising at least one compound of formula I, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier,adjuvant, or vehicle.

In some embodiments, the present invention provides the use of acompound of formula I, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of a neurologicaland/or psychiatric disorder.

EXAMPLES Example 1. Compounds

As depicted in the Examples below, in some embodiments, compounds areprepared according to the following procedures. It will be appreciatedthat, although the general methods depict the synthesis of certaincompounds of the present invention, the following methods, and othermethods known to persons skilled in the art, can be applied to allcompounds and subclasses and species of each of these, as describedherein.

Example 1.A. Preparation of 2-(2H-indazol-2-yl)ethanol (I2)

A mixture of 1H-indazole (100 g 847 mmol) in 2-bromoethanol (420 g 3.39mol) was stirred at 140° C. for 3 hour. The mixture was cooled andconcentrated. The residue was purified by flash column chromatography onsilica gel (ethyl acetate in petroleum ether, ¼ v/v) to give the desiredproduct intermediate I-2 (120 g, 87%); MS (ESI): m/z 163 [M+H]⁺.

Example 1.B. Preparation of tert-butyl2-hydroxy-2-(2-(2-hydroxyethyl)-2H-indazol-3-yl)ethyl(methyl)carbamate(I-3)

To a solution of intermediate I-2 (60 g, 0.37 mol) in THF (300 mL) at−78° C., LDA (296 mL, 2.5M, 0.74 mol) was added dropwise over 40 minuteskeeping the temperature below −78° C. the solution was allowed to cometo −15° C. when after tert-butyl methyl(2-oxoethyl)carbamate (128 g,0.74 mol) in THF (100 mL) was added dropwise over 20 minutes keeping thetemperature below −78° C. The mixture was allowed to come to rtovernight and poured into ice water, extracted with ethyl acetate (3×250mL). The combined organic layers were washed with brine (2×200 mL),dried over sodium sulfate and concentrated. The crude intermediate I-3was used in next step without purification (120 g, 65%); MS (ESI): m/z336 [M+H]⁺.

Example 1.C. Preparation of(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine(I-4)

To a solution of intermediate I-3 (120 g, 358 mmol) in toluene (400 mL)was added 4-methylbenzenesulfonic acid (123 g, 716 mmol), The reactionwas stirred at 0° C. for 3 h, then stirred at 120° C. for 16 hrs. Uponthe completion, the mixture was washed with water (3×200 mL), thenconcentrated and purified by column chromatography(Dichloromethane:methanol=1:20) to give intermediate I-4 (26 g, 33%) asa yellow oil. MS (ESI): m/z 218 [M+H]⁺; 1H NMR (400 MHz, CDCl3) δ7.68-7.65 (m, 1H), 7.56-7.54 (m, 1H), 7.29-7.26 (m, 1H), 7.06-7.02 (m,1H), 5.29-5.27 (m, 1H), 4.53-4.50 (m, 1H), 4.43-4.36 (m, 2H), 4.07-4.02(m, 1H), 3.35-3.31 (m, 1H), 3.14-3.09 (m, 1H), 2.51 (s, 3H).

Example 1.D. Preparation of (tert-butyl(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl(methyl)carbamate(I-5)

To a solution of intermediate I-4 (26 g, 120 mmol) in dichloromethane(250 mL) was added triethylamine (24.2 g, 240 mmol) and di-tert-butyldicarbonate (52.3 g, 240 mmol) at 0° C., the reaction was stirred at 0°C. for 3 h, then stirred at room temperature for 16 hrs. The mixture waswashed with water (3×200 mL), then concentrated and purified by columnchromatography (ethyl acetate/petroleum ether=1:20) to give intermediateI-5 (32 g, 80%) as a white solid. MS (ESI): m/z 280 [M-56+H]⁺.

Example 1.E. Preparation of tert-butyl(R)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carbamate(I-6) and tert-butyl(S)-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(methyl)carbamate(I-7)

Intermediate I-5 (17 g, 50.7 mmol) was separated into its enantiomersI-6 and I-7 by chiral HPLC using column CHIRALPAK IC 30*250 mm 5 μm(Daicel) and mobile phase CO₂/methanol=70/30. The flow rate was 160g/min, back pressure was 100 Bar and cycle time of stack injections was4.2 min. Intermediate I-6 (7.0 g, 41%, retention time 3.96 min) wasobtained as yellow oil and intermediate I-7 (6.5 g, 38%, retention time4.56 min) was obtained as yellow oil.

Example 1.F. Preparation of 5-8(S)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanamine(I-8)

To a solution of compound 1 (1.2 g, 4.74 mmol) in methanol (100 mL) wasadded paraformaldehyde (284.4 mg, 9.48 mmol) and NaBH₃CN (597.2 mg, 9.48mmol) and the mixture was stirred at 40° C. for 2 hours, water (100 mL)was added, extracted with dichloromethane (3×100 mL), combined, driedand then purified by preparative HPLC in 0.01% ammonia to giveintermediate I-8 (1.01 g, 92%); MS (ESI): m/z 232 [M+H]⁺; 1H NMR (400MHz, CDCl3) δ 7.67 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.31-7.27(m, 1H), 7.07-7.04 (m, 1H), 5.32-5.29 (m, 1H), 4.57-4.51 (m, 1H),4.45-4.39 (m, 2H), 4.08-4.02 (m, 1H), 3.04-3.00 (m, 1H), 2.91-2.85 (m,1H), 2.44 (s, 6H).

Example 1.G. Preparation of 5-chloro-2H-indazole (I-10)

5-amino-1H-indazole I-9 (15.41 g, 116 mmol) was suspended in a mixtureof water (250 mL), ice (250 g), and concentrated HCl (100 mL). Themixture was cooled in an ice-salt bath to an internal temperature of −5°C. To this mixture was added a solution of sodium nitrite (8.78 g, 127mmol) in water (75 mL), which had been cooled to 0° C. The resultingdiazonium solution was stirred for 15 minutes at −5° C. A solution ofcopper (I) chloride (14.9 g, 151 mmol) in concentrated HCl (150 mL) wascooled to 0° C. and then added to the diazonium solution dropwise,causing an orange precipitate to form. The cooling bath was removed toallow the reaction to warm to room temperature. Gas evolution began at10° C. internal temperature. After stirring at room temperature for 1.5hours, the gas evolution subsided. The flask was then heated to 60° C.for 30 minutes, cooled to ˜15° C. while a brown precipitate formed. Theprecipitate was collected by suction filtration and dried in a vacuumdesiccator over sodium hydroxide for 16 hours to give crude intermediateI-10 (25.6 g) as a tan powder that was purified via silicagelchromatography, eluting with dichloromethane:methanol 20:1 to giveintermediate I-10 (8.0 g, 45%); MS (ESI): m/z 153 [M+H]⁺.

Example 1.H. Preparation of 2-(5-chloro-2H-indazol-2-yl)ethanol (I-11)

Intermediate I-11 was prepared using a procedure analogous to thatdescribed for intermediate I-2, but using intermediate I-10 in place ofintermediate I-1 in the procedure of Example 1.A. (5.4 g, white solid,55%); MS (ESI): m/z 197 [M+H]⁺.

Example 1.I. Preparation of tert-butyl(2-(5-chloro-2-(2-hydroxyethyl)-2H-indazol-3-yl)-2-hydroxyethyl)(methyl)carbamate(I-12)

A solution of 2.5 M butyllithium in hexane (5.4 mL, 13.53 mmol) wasadded to a solution of intermediate I-11 (1.21 g, 6.15 mmol) intetrahydrofuran (15 mL) at −78° C. The solution was stirred at −78° C.for 30 min and then tert-butyl methyl(2-oxoethyl)carbamate (2.13 g,12.13 mmol) was added, the reaction mixture was warmed slowly to roomtemperature. After stirring for 2 h, H₂O (15 mL) was added, the waterphase was extracted by ethyl acetate (30 mL) twice, the organic phasewas washed by brine and dried over Na₂SO₄, the solvent was removed invacuo and the residue was purified by reverse-phase columnchromatography to give intermediate I-12 (880 mg black oil, purity: 62%,214 nm, 24%) that was used in the following step without furtherpurification. MS (ESI): m/z 370 [M+H]⁺.

Example 1.J. Preparation of1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanamine(I-13)

Intermediate I-13 was prepared using a procedure analogous to thatdescribed for intermediate I-4, but using intermediate I-12 in place ofintermediate I-3 in the procedure of Example 1.C. as the startingmaterial. (435 mg, colorless oil), MS (ESI): m/z 252 [M+H]⁺. ¹H-NMR (400MHz, CDCl₃): δ 7.60 (d, J=9.4 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.24-7.18(m, 1H), 5.23 (dd, J=7.9, 2.9 Hz, 1H), 4.58-4.47 (m, 1H), 4.45-4.36 (m,2H), 4.06 (ddd, J=12.0, 9.8, 3.6 Hz, 1H), 3.28 (dd, J=13.0, 3.1 Hz, 1H),3.10 (dd, J=12.8, 8.0 Hz, 1H), 2.53 (s, 3H).

Example 1.K. Preparation of1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanamine(I-14)

Intermediate I-14 was prepared using a procedure analogous to thatdescribed for intermediate I-8, but using compound 5 in place ofcompound 1 in the procedure of Example 1.F. as the starting material.(120 mg, white solid); MS (ESI): m/z 265 [M+H]⁺; ¹H-NMR (400 MHz,CDCl₃): δ 7.60 (d, J=9.4 Hz, 2H), 7.21 (dd, J=9.1, 2.0 Hz, 1H), 5.24(dd, J=8.3, 3.4 Hz, 1H), 4.58-4.48 (m, 1H), 4.42 (td, J=5.3, 2.7 Hz,2H), 4.10-4.01 (m, 1H), 2.95 (dd, J=13.4, 3.6 Hz, 1H), 2.86 (dd, J=13.4,8.4 Hz, 1H), 2.44 (s, 6H).

Example 1.L. Preparation of5-fluoro-2-(2-hydroxyethyl)-2H-indazole-3-carbaldehyde (I-16)

To a solution of intermediate I-15 (1.9 g, 10.6 mmol, prepared using aprocedure analogous to that described for intermediate I-2, but using5-fluoro-1H-indazole in place of intermediate I-1 in the procedure ofExample 1.A. in tetrahydrofuran (100 mL) at −78° C., n-butyllithium(13.2 mL, 31.7 mmol) was added dropwise. The resulting mixture wasstirred at −78° C. for 30 min then warmed to −20° C. for 0.5 h and asolution of N,N-dimethylformamide (1.15 g, 15.9 mmol) in tetrahydrofuran(5 mL) was added dropwise. The resulting mixture was stirred at −78° C.for 1 h. Upon the completion, the reaction mixture was neutralized withsaturated ammonium chloride solution and extracted with ethyl acetate(3×100 mL). The combined organic layers were washed with brine (200 mL),the solvent was removed to give intermediate I-16 (2.2 g) as a yellowoil that was used in the following step without further purification. MS(ESI): m/z 209 [M+H]⁺.

Example 1.M. Preparation of9-fluoro-1-methoxy-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole (I-17)

To a solution of intermediate I-16 (2.2 g, 10.6 mmol) andtrimethoxymethane (5.6 g, 53.0 mmol) in methanol (50 mL),p-toluenesulfonic acid (5.0 g, 26.5 mmol) was added in portions. Theresulting mixture was stirred at 45° C. for 1.5 h. Upon the completion,the reaction mixture was neutralized with saturated sodium bicarbonatesolution and extracted with dichloromethane (3×80 mL). The combinedorganic layers were washed with brine (150 mL), dried over sodiumsulfate and concentrated and purified by flash column chromatography onsilica gel (dichloromethane/petroleum ether, 1/1 v/v) to give thedesired product intermediate I-17 (1.4 g, 60%) as a yellow oil. MS(ESI): m/z 223 [M+H]⁺.

Example 1.N. Preparation of9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole-1-carbonitrile(I-18)

To a solution of intermediate I-17 (1.4 g, 6.3 mmol) andtrimethylsilylcyanide (3.9 ml, 31.5 mmol) in dichloromethane (50 mL) at−78° C. boron trifluoride etherate (3.9 ml, 31.5 mmol) was addeddropwise over the course of 10 min. The resulting mixture was stirred at30° C. for 1.5 h. Upon the completion, the reaction mixture wasneutralized with saturated sodium bicarbonate solution, extracted withdichloromethane (3×60 mL). The combined organic layers were washed withbrine (100 mL), dried over sodium sulfate, concentrated and purified byflash column chromatography on silica gel (dichloromethane/methanol,100/5 v/v) to give intermediate I-18 (0.40 g, 29%) as a yellow solid. MS(ESI): m/z 218 [M+H]⁺.

Example 1.O. Preparation of(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanamine(I-19)

To a solution of intermediate I-18 (0.40 g, 1.84 mmol) intetrahydrofuran (20 mL) was added lithium tetrahydridoaluminate (0.11 g,2.76 mmol). The mixture was stirred at 0° C. for 10 minutes and warmedto room temperature, the mixture was stirred at room temperature for 0.5hour. After completion, the reaction was quenched with water (30 mL),diluted with dichloromethane (3×30 mL) and washed with brine (3×30 mL),dried over sodium sulfate, filtered and concentrated in vacuo to givecrude intermediate I-19 (0.3 g, yellow oil) that was used in thefollowing step without further purification. MS (ESI): m/z 222 [M+H]⁺.

Example 1.P. Preparation of tert-butyl(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methylcarbamate(I-20)

Intermediate I-20 was prepared using a procedure analogous to thatdescribed for intermediate I-5, but using intermediate I-19 in place ofintermediate I-4 in the procedure of Example 1.D. (0.20 g, yellow oil);MS (ESI): m/z 322 [M+H]⁺.

Example 1.Q. Preparation of tert-butyl((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)(ethyl)carbamate (I-22)

To a solution of intermediate I-21 (319 mg, 1.05 mmol, prepared using aprocedure analogous to that described for intermediate I-20 but usingintermediate I-2 in place of intermediate I-15 in the procedure ofExample 1.L) in N,N-dimethyllformamide (10 mL) was added sodium hydride(60% in oil, 63 mg, 1.58 mmol) at 0° C. The reaction was stirred at 0°C. for 1 hour. Iodoethane (164 mg, 1.05 mmol) was added. The reactionwas stirred at ambient temperature for 3 hours. Saturated aqueous sodiumbicarbonate (50 mL) and ethyl acetate (60 mL) were added and the organicphase was washed with water (2×30 mL) and brine (3×60 mL). The combinedorganics were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give intermediate I-22 (256 mg, amber oil, 74%)that was used in the following step without further purification. MS(ESI): m/z 332 [M+H]⁺.

Example 1.R. Preparation of1-(2-(2-hydroxyethyl)-2H-indazol-3-yl)ethanone (I-23)

Intermediate I-23 was prepared using a procedure analogous to thatdescribed for intermediate I-12, but using intermediate I-2 in place ofintermediate I-11 and ethyl acetatein place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.I. (6.1 g,brown oil); MS (ESI): m/z 205 [M+H]⁺.

Example 1.S. Preparation of 2-(3-acetyl-2H-indazol-2-yl)ethyl acetate(I-24)

To a solution of intermediate I-23 (6.1 g, 29.87 mmol) indichloromethane (200.0 mL) was added acetyl chloride (1.88 g, 23.9 mmol)in one portion at room temperature. To reaction mixture was addedtriethylamine (3.02 g, 29.87 mmol) dropwise under nitrogen at 0° C. over15 min. The reaction mixture was stirred for 1.0 h at room temperature.The reaction mixture was quenched with sodium hydrogen carbonate aqueoussolution (50 mL). The aqueous phase was extracted with dichloromethane(50 mL×3). The combined organic phase was washed with brine (70 mL×3)and dried over sodium sulphate and concentrated under reduced pressureto afford the crude product which was purified through silica gel.(Petroleum ether:ethyl acetate=5:1) to give intermediate I-24 (0.9 g31%)as a brown oil. MS (ESI): m/z 247 [M+H]⁺.

Example 1.T. Preparation of 2-(3-(2-bromoacetyl)-2H-indazol-2-yl)ethylacetate (I-25)

To a solution of intermediate I-24 (0.72 g, 2.92 mmol) in a mixture ofglacial acetic acid (2.5 mL) and HBr/glacial acetic acid (2.5 mL) wasadded bromine (0.51 g, 3.21 mmol) dropwise under nitrogen at 0° C. over10 min and the reaction mixture was stirred at 40° C. for 1.0 h. Thereaction mixture was poured into 150 g of ice and neutralized with solidsodium carbonate to pH=7. The aqueous phase was extracted withdichloromethane (50 mL×3). The combined organic phase was washed withbrine (50 mL×3), dried over sodium sulphate and concentrated underreduced pressure to afford intermediate I-25 (0.95 g, 100%) as a brownsolid. MS (ESI): m/z 325, 327 [M+H]⁺.

Example 1.U. Preparation of1-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)pyrrolidin-1-iumchloride (I-26)

To a solution of intermediate I-25 (0.652 g, 2.00 mmol) in acetonitrile(50 mL) was added pyrrolidine (4.9 ml, 60.0 mmol) dropwise at −50° C.and the reaction mixture was stirred at room temperature for 2.0 h andthen diluted with 25 mL of methanol. To the reaction mixture was addedsodium borohydride (0.304 g, 8.0 mmol) portion wise at room temperature.After 1.0 h, the reaction mixture was quenched with 50.0 mL of sat.NH₄Cl solution and the crude reaction mixture was concentrated underreduced pressure. The residue was dissolved in ethyl acetate (150 mL),washed with brine (50 mL×3), the organic phase was dried over sodiumsulphate, the solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in asolution of methylamine in methanol (40.0 mL, 30%) at room temperatureand the solution was stirred at 70° C. for 3.0 h. The reaction mixturewas concentrated under reduced pressure. 4-methyl benzenesulfonic acid(1.548 g, 9.0 mmol) was added to the solution of the residue in toluene(35.0 mL) in one portion at room temperature and the reaction mixturewas stirred at reflux for 16 hrs. The reaction mixture was poured intosaturated sodium carbonate aqueous solution (80.0 mL). The resultedmixture was extracted with ethyl acetate (80.0 mL×3). The organic phasewas washed with brine (70.0 mL×3) and concentrated under reducedpressure to afford the crude product which was purified through silicagel. (Dichloromethane:methanol=30:1) to give intermediate I-26 (87 mg,17%) as a brown solid. MS (ESI): m/z 258 [M+H]⁺.

Example 1.V. Preparation of3,4-dihydrospiro[[1,4]oxazino[4,3-b]indazole-1,3′-pyrrolidin]-1′-iumchloride (I-27)

Intermediate I-27 was prepared using a procedure analogous to thatdescribed for compound 5 but using intermediate I-2 in place ofintermediate I-11 and tert-butyl 3-oxopyrrolidine-1-carboxylate in placeof tert-butyl methyl(2-oxoethyl)carbamate in the procedure of Example1.I (740 mg, 91%) as a white solid. MS (ESI): m/z 230 [M+H]+.

Example 1.W. Preparation of(R)-1-((R)-4-methylmorpholin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole(I-29) and(S)-1-((R)-4-methylmorpholin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole(I-30)

Intermediate I-28 was prepared using a procedure analogous to thatdescribed for compound 24 but using (R)-tert-butyl2-formylmorpholine-4-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.I. The twodiastereomers 1-29 and I-30 were separated by preparative HPLC toprovide intermediate I-29 (340 mg) and intermediate I-30 (420 mg).

Example 1.X. Preparation of tert-butyl(+/−)-((R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethyl)carbamate(I-32) and(+/−)-tert-butyl((S)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethyl)carbamate(I-33)

To a solution of intermediate I-31 (3.91 g, 11.53 mmol, prepared using aprocedure analogous to that described for intermediate I-25 but usingintermediate I-2 in place of intermediate I-11 and methyl propionate inplace of tert-butyl methyl(2-oxoethyl)carbamate in the procedure ofExample 1.1) in a mixture of acetonitrile (50.0 mL) and methanol (10.0mL) was added a solution of NH₃ in methanol (20.0 M) (80.0 mL) dropwiseat −78° C. and the reaction mixture was stirred at room temperature for5.0 h. Sodium tetrahydroborate (1.1 g, 29.0 mmol) was added portion-wiseto the reaction mixture at room temperature over 5.0 min. After 1 h, thereaction was quenched with water (50.0 mL) and concentrated underreduced pressure. The residue was dissolved in toluene (250.0 mL) and tothis solution was added 4-methylbenzenesulfonic acid (19.4 g, 112.5mmol) in one portion at room temperature. The reaction mixture wasstirred at reflux for 16 hrs, concentrated under reduced pressure, theresidue was dissolved in methanol (300 mL) and neutralized with solidsodium carbonate (11.93 g, 112.5 mmol). To this mixture was addedtriethylamine (0.96 g, 9.5 mmol) and di-tert-butyl dicarbonate (3.69 g,16.95 mmol) in one portion at room temperature, the reaction mixture wasstirred at room temperature for 1.5 h and concentrated under reducedpressure. The residue was dissolved in dichloromethane (500.0 mL),washed with brine (150.0 mL×3), the organic phase was concentrated underreduced pressure to afford the crude product which was purified throughsilica gel. (dichloromethane:methanol=50:1) and then by preparative TLC(dichloromethane:methanol=30:1) to provide the low polarity intermediateI-32 (677 mg, yellow solid, 18%), MS (ESI): m/z 318 [M+H]⁺ and the highpolarity intermediate I-33 (360 mg, yellow solid, 10%), MS (ESI): m/z318 [M+H]⁺.

Example 1.Y. Preparation of (+/−)-tert-butyl((R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethyl)(methyl)carbamate(I-34)

To a solution of intermediate I-32 (550.0 mg, 1.73 mmol) in a mixture ofN,N-dimethylformamide (5.0 mL) and tetrahydrofuran (5.0 mL) was addedsodium hydride (60% in oil, 0.139 g, 3.47 mmol) and iodomethane (0.22mL, 3.47 mmol) in one portion at room temperature and the reactionmixture was stirred at room temperature for 1.0 h. The reaction mixturewas quenched with an aqueous solution of NH₄Cl (10 mL), diluted withdichloromethane (50 mL) and washed with brine (30 mL×3). The organicphase was dried over sodium sulphate and concentrated under reducedpressure to afford intermediate I-34 (0.574 g, 100%) as a brown solid.MS (ESI): m/z 332 [M+H]⁺.

Example 1.Z. Preparation of tert-butyl3-hydroxy-3-(2-(2-(methylsulfonyloxy)ethyl)-2H-indazol-3-yl)azetidine-1-carboxylate(I-36)

To a solution of intermediate I-35 (prepared using a procedure analogousto that described for intermediate I-3 but using tert-butyl3-oxoazetidine-1-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B. (420 mg,1.26 mmol) in ethyl acetate (20 ml) was added triethylamine (0.48 g,4.72 mmol) and the solution was cooled to 0° C. Methanesulfonyl chloride(0.14 g, 1.26 mmol) was added in several portions, the reaction mixturewas stirred at 0° C. for 2 hrs and quenched with 30 ml of water. Thecrude reaction mixture was extracted with ethyl acetate (3×30 mL), thecombined organic phase was dried over sodium sulfate and solids wereremoved by filtration. The filtrate was concentrated in vacuo to giveintermediate I-36 (440 mg, 68%, white solid). MS (ESI): m/z 412.1[M+H]⁺.

Example 1.AA. Preparation of(+/−)-1-((S)-morpholin-3-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole(I-37)

Intermediate I-37 was prepared using a procedure analogous to thatdescribed for intermediate I-4 but using (S)-tert-butyl3-formylmorpholine-4-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B. (1.09 g,brown oil); MS (ESI): m/z 260 [M+H]⁺.

Example 1.AB. Preparation of tert-butyl (+/−)-(3S)-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholine-4-carboxylate(I-38)

Intermediate I-38 was prepared using a procedure analogous to thatdescribed for intermediate I-5 but using intermediate I-37 in place ofintermediate I-4 in the procedure of Example 1.D. (0.72 g, colorlessoil); MS (ESI): m/z 360 [M+H]⁺.

Example 1.AC. Preparation of tert-butyl(+/−)-(S)-3-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholine-4-carboxylate(I-39) and tert-butyl(+/−)-(S)-3-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholine-4-carboxylate(I-40)

Cis/trans diastereomers of intermediate I-38 were separated by HPLC toprovide intermediate I-39 (0.3 g, colorless oil) and intermediate I-40(0.21 g, colorless oil).

Example 1.AD. Preparation of 3-(2H-indazol-2-yl)propan-1-ol (I-41)

Intermediate I-41 was prepared using a procedure analogous to thatdescribed for intermediate I-2 but using 3-bromopropan-1-ol in place of2-bromoethanol in the procedure of Example 1.A. (51.4 g, brown oil); MS(ESI): m/z 177 [M+H]⁺.

Example 1.AE. Preparation of2-(3-(tert-butyldimethylsilyloxy)propyl)-2H-indazole (I-42)

To a solution of intermediate I-41 (30 g, 170 mmol) inN,N-dimethylformamide (400 mL) was added tert-butylchlorodimethylsilane(38.4 g, 255 mmol) and 1H-imidazole (23.1 g, 340 mmol). The reactionmixture was stirred at room temperature for 16 h, concentrated in vacuoand the residue was purified by silica-gel chromatography (petroleumether:EtOAc 9:1) to provide intermediate I-42. (39.7 g, 81%, orangeoil); MS (ESI): m/z 291 [M+H]⁺.

Example 1.AF. Preparation of tert-butyl2-(2-(3-(tert-butyldimethylsilyloxy)propyl)-2H-indazol-3-yl)-2-hydroxyethyl(methyl)carbamate(I-43)

Intermediate I-43 was prepared using a procedure analogous to thatdescribed for intermediate I-12 but using intermediate I-42 in place ofintermediate I-11 in the procedure of Example 1.I. (11 g, orange oil);MS (ESI): m/z 464 [M+H]⁺.

Example 1.AG. Preparation of tert-butyl2-hydroxy-2-(2-(3-hydroxypropyl)-2H-indazol-3-yl)ethyl(methyl)carbamate(I-44)

To a solution of intermediate I-43 (1.0 g, 2.16 mmol) in tetrahydrofuran(10 mL) was added tetrabutylammonium fluoride (0.52 g, 2.16 mmol) andthe reaction mixture was stirred at ambient temperature overnight. Thecrude reaction mixture was extracted with ethyl acetate, the combinedorganic layers were dried with Na₂SO₄. Solids were removed by filtrationand the filtrate was concentrated in vacuo. The resulting oil waspurified by flash column chromatography (dichloromethane/methanol=20/1)to provide intermediate I-44. (500 mg, 66.2%, yellow oil); MS (ESI): m/z350 [M+H]⁺.

Example 1.AH. Preparation ofN-methyl(1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methanamine(I-45)

Intermediate I-45 was prepared using a procedure analogous to thatdescribed for intermediate I-4 but using intermediate I-44 in place ofintermediate I-3 in the procedure of Example 1.C. MS (ESI): m/z 232[M+H]⁺.

Example 1.AI. Preparation of tert-butylmethyl((1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)carbamate(I-46)

Intermediate I-46 was prepared using a procedure analogous to thatdescribed for intermediate I-5 but using intermediate I-45 in place ofintermediate I-4 in the procedure of Example 1.D. (4.0 g, orange oil);MS (ESI): m/z 332 [M+H]⁺.

Example 1.AJ. Preparation of2-(3-hydroxypropyl)-2H-indazole-3-carbaldehyde (I-47)

Intermediate I-47 was prepared using a procedure analogous to thatdescribed for intermediate I-16 but using intermediate I-41 in place ofintermediate I-15 in the procedure of Example 1.L. (5.5 g, yellow oil);MS (ESI): m/z 286 [M+H]⁺.

Example 1.AK. Preparation of2-(2-(3-hydroxypropyl)-2H-indazol-3-yl)-2-(trimethylsilyloxy)acetonitrile(I-48)

To a solution of intermediate I-47 (3.17 g, 15.5 mmol) in methanol (40mL) was added zinc(II) iodide (4.94 g, 15.5 mmol) andtrimethylsilanecarbonitrile (3.07 g, 31 mmol). The reaction mixture wasstirred at room temperature for 1 h, concentrated in vacuo, the cruderesidue used in the following step without further purification.

Example 1.AL. Preparation of3-(3-(2-amino-1-hydroxyethyl)-2H-indazol-2-yl)propan-1-ol (I-49)

To a solution of intermediate I-48 (5.9 g, 19.6 mmol) in tetrahydrofuran(100 mL) was added Lithium aluminum hydride (1.48 g, 39.2 mmol) and thereaction mixture was stirred at room temperature for 1 h. Water (20 mL)was added, solids were removed by filtration and the filtrate wasconcentrated in vacuo. The crude residue was used for in the followingstep without further purification. MS (ESI): m/z 236 [M+H]⁺.

Example 1.AM. Preparation of(1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methanamine (I-50)

Intermediate I-50 was prepared using a procedure analogous to thatdescribed for intermediate I-4 but using intermediate I-49 in place ofintermediate I-3 in the procedure of Example 1.C. MS (ESI): m/z 218[M+H]⁺.

Example 1.AN. Preparation of tert-butyl(1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methylcarbamate(I-51)

Intermediate I-51 was prepared using a procedure analogous to thatdescribed for intermediate I-5 but using intermediate I-50 in place ofintermediate I-4 in the procedure of Example 1.D. (160 mg); MS (ESI):m/z 318 [M+H]⁺.

Example 1.AO. Preparation of tert-butylethyl((1,3,4,5-tetrahydro-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)carbamate(I-52)

To a solution of intermediate I-51 (140 mg, 441 μmol) in N,N-Dimethylformamide (5 mL) was added sodium hydride (27 mg, 1.12 mmol) andiodoethane (232 mg, 1.49 mmol) and the reaction was stirred at roomtemperature for 3 h. Water (5 mL) was added followed by ethyl acetate(20 mL) and the resulting biphasic mixture was transferred to aseparatory funnel. The layers were separated and the organic phase waswashed with water (2×10 mL) and brine (2×10 mL). The combined organiclayers were dried over anhydrous sodium sulfate, solids were removed byfiltration and the filtrate was concentrated in vacuo. The residue waspurified by preparative thin layer chromatography with petrolether/ethyl acetate=3/1 to provide intermediate I-52. (120 mg, 79%,clear oil); MS (ESI): m/z 346 [M+H]⁺.

Example 1.AP. Preparation of 3-bromothiophene-2-carbaldehyde (I-53)

To a solution of 3-bromothiophene (25 g, 153 mmol) in tetrahydrofuran(250 mL) was added 2 M Lithium diisopropylamide in tetrahydrofuran (77mL, 154 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for1 h. N,N-dimethylformamide (12.2 g, 168 mmol) was added and the reactionmixture was allowed to warm to room temperature and stirred foradditional 2 h. Water (100 mL) was added and extracted with ethylacetate (500 mL×3) was performed. The combined organic layer were driedover anhydrous magnesium sulfate, solids were removed by filtration andthe filtrate was concentrated by evaporation in vacuo. The residue waspurified by silica gel chromatography (petrol ether/ethyl acetate=10/1)to provide intermediate I-53 (20 g, 68%). MS (ESI): m/z 190 [M+H]⁺.

Example 1.AQ. Preparation of 3-azidothiophene-2-carbaldehyde (I-54)

To a solution of intermediate I-53 (2.0 g, 10.47 mmol) in dimethylsulfoxide (15 mL) was added sodium azide (2.72 g, 41.88 mmol) and thesolution was stirred at 80° C. for 4 h. Water (100 mL) was added, theaqueous layer was extracted by ethyl acetate (2×100 mL), the organicphase was washed by brine and dried over anhydrous sodium sulfate.Solids were removed by filtration, and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatography (petrolether/ethyl acetate=5/1) to provide intermediate I-54 (840 mg, 52%). MS(ESI): m/z 154 [M+H]⁺.

Example 1.AR. Preparation of 2-(2H-thieno[3,2-c]pyrazol-2-yl)ethanol(I-55)

To a solution of intermediate I-54 (1.45 g, 9.47 mmol) in toluene (20mL) was added 2-aminoethanol (1.16 g, 18.94 mmol) and the reactionmixture was stirred at 120° C. for 3 h. The crude reaction mixture wasconcentrated in vacuo, water (20 mL) was added, the aqueous phase wasextracted by ethyl acetate (2×50 mL), the combined organic layers werewashed with brine (50 mL) and the dried over anhydrous sodium sulfate.Solids were removed by filtration, the filtrate was concentrated invacuo and the residue was purified by silica gel column chromatography(petrol ether:ethyl acetate=5:1) to provide intermediate I-55. (400 mg,25%, yellow oil); MS (ESI): m/z 169 [M+H]⁺.

Example 1.AS. Preparation of tert-butyl2-hydroxy-2-(2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazol-3-yl)ethyl(methyl)carbamate(I-56)

Intermediate I-56 was prepared using a procedure analogous to thatdescribed for intermediate I-3 but using intermediate I-55 in place ofintermediate I-2 in the procedure of Example 1.B. (170 mg, 12%, whitesolid); MS (ESI): m/z 342 [M+H]⁺.

Example 1.AT. Preparation of1-(7,9-dihydro-6H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-methylmethanamine(I-57)

Intermediate I-57 was prepared using a procedure analogous to thatdescribed for intermediate I-4 but using intermediate I-56 in place ofintermediate I-3 in the procedure of Example 1.C. MS (ESI): m/z 224[M+H]⁺.

Example 1.AU. Preparation of tert-butyl((7,9-dihydro-6H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methyl)(methyl)carbamate(I-58)

Intermediate I-58 was prepared using a procedure analogous to thatdescribed for intermediate I-5 but using intermediate I-57 in place ofintermediate I-4 in the procedure of Example 1.D. (95 mg, white solid);MS (ESI): m/z 324 [M+H]⁺.

Example 1.AV. Synthesis of2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazole-3-carbaldehyde (I-59)

Intermediate I-59 was prepared using a procedure analogous to thatdescribed for intermediate I-16 but using intermediate I-55 in place ofintermediate I-15 in the procedure of Example 1.L. (600 mg, yellow oil);MS (ESI): m/z 197 [M+H]⁺.

Example 1.AW. Synthesis of2-(2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazol-3-yl)-2-(trimethylsilyloxy)acetonitrile(I-60)

Intermediate I-60 was prepared using a procedure analogous to thatdescribed for intermediate I-48 but using intermediate I-59 in place ofintermediate I-47 in the procedure of Example 1.AK.

Example 1.AX. Synthesis of2-amino-1-(2-(2-hydroxyethyl)-2H-thieno[3,2-c]pyrazol-3-yl)ethanol(I-61)

Intermediate I-61 was prepared using a procedure analogous to thatdescribed for intermediate I-49 but using intermediate I-60 in place ofintermediate I-48 in the procedure of Example 1.AL. MS (ESI): m/z 228[M+H]⁺.

Example 1.AY. Synthesis of(7,9-dihydro-6H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methanamine(I-62)

Intermediate I-62 was prepared using a procedure analogous to thatdescribed for intermediate I-4 but using intermediate I-61 in place ofintermediate I-3 in the procedure of Example 1.C. MS (ESI): m/z 210[M+H]⁺.

Example 1.AZ. Synthesis of tert-butyl((7,9-dihydro-6H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methyl)carbamate(I-63)

Intermediate I-63 was prepared using a procedure analogous to thatdescribed for intermediate I-5 but using intermediate I-62 in place ofintermediate I-4 in the procedure of Example 1.D. (165 mg, 12%, yellowoil); MS (ESI): m/z 310 [M+H]⁺.

Example 1.BA. Synthesis of N-(4-methylpyridin-3-yl)acetamide (I-64)

Into a 250 mL round bottom flask was placed a solution of4-methylpyridin-3-amine (10 g, 92.47 mmol, 1.00 equiv) in aceticanhydride (50 mL). The resulting solution was stirred for 1 hour at roomtemperature. Water (200 ml) was added, the pH of the solution wasadjusted to 7 by addition of sodium carbonate (1M solution in water).The crude reaction mixture was extracted with ethyl acetate (3×300 ml),the combined organic layers were dried over anhydrous sodium sulfate,solids were removed by filtration and the filtrate was concentrated invacuo. The residue was purified by silicagel-gel chromatography(dichloromethane/methanol: 20/1) to provide intermediate I-64. (12 g,94%); MS (ESI): m/z 151 [M+H]⁺.

Example 1.BB. Synthesis of Preparation of tert-butyl3-(3-acetamidopyridin-4-yl)-2-hydroxypropyl(methyl)carbamate (I-65)

To a solution of intermediate I-64 (2.5 g) in dry THF (70 mL) at −78° C.under argon was added n-BuLi (17 mL, 2.5 M in hexanes) and the reactionmixture was stirred at −78° C. for 15 min and then at −25° C. foradditional 90 min. The reaction mixture was cooled to −78° C. and asolution of tert-butyl methyl(2-oxoethyl)carbamate (3.46 g) in drytetrahydrofuran (20 mL) was added drop-wise. The reaction mixture wasstirred at −78° C. for 10 min and then at −20° C. for additional 3 h. Asaturated aqueous solution of ammonium chloride was added to quenchexcess n-BuLi. The crude reaction mixture was concentrated in vacuo,water was added to the residue and extraction with dichloromethane (4×50mL) was performed. The combined organic layers were dried over anhydrousNa₂SO₄, solids were removed by filtration and the filtrate wasconcentrated in vacuo. The orange oily residue was purified by silicagelchromatography (dichloromethane/methanol 50/1) to provide intermediateI-65. (2.69 g, 50%, light-yellow oil); MS (ESI): m/z 324 [M+H]⁺.

Example 1.BC. Synthesis of1-(1-acetyl-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-(tert-butoxycarbonyl(methyl)amino)ethylacetate (I-66)

To a suspension of intermediate I-65 (1.0 g, 3.09 mmol) in dry toluene(30 mL) under argon were added potassium acetate (314 mg, 2.0 mmol) andacetic anhydride (0.8 mL, 8.1 mmol). The reaction mixture was stirred at80° C. while isoamyl nitrite (1.1 mL, 7.72 mmol) was added drop-wise andthe reaction mixture was heated at 100° C. for 16 h. Solids were removedby filtration, the residue was washed with hot toluene and the combinedfiltrates were concentrated in vacuo to afford intermediate I-66 thatwas used in the following step without further purification. (1.0 g,dark oil); MS (ESI): m/z 377 [M+H]⁺.

Example 1.BD. Synthesis of tert-butyl2-(2-hydroxyethoxy)-2-(2H-pyrazolo[3,4-c]pyridin-3-yl)ethyl(methyl)carbamate(I-67)

To a solution of intermediate I-66 (1.8 g, 4.78 mmol) in ethane-1,2-diol(10 mL) was added sodium hydroxide (0.57 g, 14.34 mmol) and the reactionmixture was stirred at ambient temperature for 24 h. Ethyl acetate (100mL) was added and extraction was performed. The combined organic layerswere washed with brine (3×20 mL), dried over anhydrous sodium sulfate,solids were removed by filtration and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatography(dichloromethane/methanol) to provide intermediate I-67 (0.03 g, 2%,oil); MS (ESI): m/z 337 [M+H]⁺.

Example 1.BE. Synthesis of tert-butyl((3,4-dihydro-1H-pyrido[3′,4′:3,4]pyrazolo[5,1-c][1,4]oxazin-1-yl)methyl)(methyl)carbamate(I-68)

To a solution of intermediate I-67 (500 mg) and triphenylphosphine (776mg) in dry tetrahydrofuran (50 mL) at 0° C. under argon was added DIAD(600 mg) and the reaction mixture was stirred at room temperature for 12h. Water (30 mL) and ethyl acetate (2×100 mL) were added and extractionwas performed. The combined organic layers were washed with brine (2×30mL), dried over anhydrous sodium sulfate, solids were removed byfiltration and the filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether/ethyl acetate) toprovide intermediate I-68. (300 mg, 64%, white solid); MS (ESI): m/z 319[M+H]⁺.

Example 1.BF. Preparation of tert-butyl(S)-2-(2-(2-hydroxyethyl)-2H-indazole-3-carbonyl)-azetidine-1-carboxylate(I-69)

A solution of intermediate I-2 (3.24 g, 19.9 mmol) in THF (60 mL) wascooled to −78° C., a solution of n-BuLi (4.45 g, 69.6 mmol 2.5M inhexanes) was added dropwise and the reaction mixture was stirred at −78°C. for 1 hr. A solution of (S)-tert-butyl2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (4.86 g, 19.9 mmol)in THF (30 mL) was added to the mixture and allowed to warm to roomtemperature over the course of 1 hr. The reaction mixture was quenchedwith brine (50 mL), extracted with ethyl acetate (50 mL×3), the combinedorganic phase was dried over Na₂SO₄, solids were removed by filtration,the filtrate was concentrated in vacuo and the residue was purified bysilicagel chromatography to give intermediate I-69 (552 mg, 8%) as ayellow oil. MS (ESI): m/z 346 [M+H]⁺.

Example 1.BG. Preparation of tert-butyl(2S)-2-(hydroxy(2-(2-hydroxyethyl)-2H-indazol-3-yl)methyl)azetidine-1-carboxylate(I-70)

To a solution of intermediate I-69 (700 mg, 2.02 mmol) in MeOH (10 mL)was added solid NaBH₄ (76.4 mg, 2.02 mmol) and the reaction mixture wasstirred at ambient temperature for 16 hrs. The crude reaction mixturewas concentrated in vacuo and the residue was purified by silicagelchromatography to give intermediate I-70 (402 mg, 57%) as yellow oil. MS(ESI): m/z 348 [M+H]⁺.

Example 1.BH. Preparation of tert-butyl (2S)-2-(hydroxy(2-(2-((methylsulfonyl)oxy)ethyl)-2H-indazol-3-yl)methyl)azetidine-1-carboxylate(I-71)

Intermediate I-71 was prepared using a procedure analogous to thatdescribed for intermediate I-36 but using intermediate I-70 in place ofintermediate I-35 in the procedure of Example 1.Z. (497 mg, 45%) asyellow oil. MS (ESI): m/z 426 [M+H]⁺.

Example 1.1. Preparation of(S)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminiumchloride (1)

To a solution of intermediate I-7 (2.0 g, 6.0 mmol) in dichloromethane(20 mL) was added 4 M HCl/methanol (8 mL) dropwise, the resultingsolution was stirred for 10 min and concentrated to give compound 1(1.30 g, 86%) as a white solid. MS (ESI): m/z 218 [M+H]⁺, ¹H-NMR (400MHz, MeOD): δ 7.68-7.71 (d, J=8.4 Hz, 1H), 7.48-7.57 (m, 2H), 7.23-7.27(m, 1H), 5.61-5.63 (m, 1H), 4.36-4.53 (m, 3H), 4.08-4.14 (m, 1H),3.77-3.81 (m, 1H), 3.50-3.56 (m, 1H), 2.67 (s, 3H).

Example 1.2. Preparation of(R)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminiumchloride (2)

Compound 2 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-6 in place of intermediate I-7in the procedure of Example 1.1. (1.25 g, white solid); MS (ESI): m/z218 [M+H]; ¹H-NMR (400 MHz, MeOD): δ 7.64-7.66 (d, J=8.8 Hz, 1H),7.46-7.55 (m, 2H), 7.19-7.24 (m, 1H), 5.56-5.59 (m, 1H), 4.38-4.71 (m,3H), 4.09-4.15 (m, 1H), 3.76-3.81 (m, 1H), 3.50-3.56 (m, 1H), 2.71 (s,3H).

Example 1.3.Preparation of 5-9(S)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanaminiumchloride (3)

To a solution of intermediate I-8 (1.0 g, 4.33 mmol) in dichloromethane(20 mL) was added 4 M HCl/methanol (8 mL) dropwise, the resultingsolution was stirred for 2 min and concentrated to give compound 3 (1.1g, 86%) as a white solid. MS (ESI): m/z 232 [M+H]⁺, ¹H-NMR (400 MHz,MeOD): δ 7.58-7.64 (m, 2H), 7.42-7.44 (d, J=6.8 Hz, 1H), 7.18 (s, 1H),5.64-5.69 (m, 1H), 4.39-4.53 (m, 3H), 4.11-4.17 (m, 1H), 3.88-3.91 (d,J=13.2 Hz, 1H), 3.59-3.65 (m, 1H), 3.02 (s, 3H), 2.87 (s, 3H).

Example 1.4. Preparation of(R)-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanaminiumchloride (4)

Compound 4 was prepared using a procedure analogous to that describedfor compound 3 but using compound 2 in place of compound 1 in theprocedure of Example 1.F. (1.1 g, white solid); MS (ESI): m/z 232[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 7.51-7.53 (m, 2H), 7.33-7.37 (m, 1H),7.10-7.13 (m, 1H), 5.44-5.47 (m, 1H), 4.28-4.44 (m, 3H), 4.03-4.09 (m,1H), 3.78-3.82 (m, 1H), 3.46-3.52 (m, 1H), 2.99 (s, 3H), 2.86 (s, 3H).

Example 1.5. Preparation of1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminiumchloride (5)

Compound 5 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-13 in place of intermediate I-8in the procedure of Example 1.3. (145 mg, white solid); MS (ESI): m/z252 [M+H]⁺.

Example 1.6. Preparation of1-(9-chloro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanaminiumchloride (6)

Compound 6 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-14 in place of intermediate I-8in the procedure of Example 1.3. (115 mg, white solid); MS (ESI): m/z265 [M+H]⁺.

Example 1.7. Preparation of1-(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminiumchloride (7)

Compound 7 was prepared using a procedure analogous to that describedfor compound 5 but using 5-fluoro-1H-indazole in place of 1H-indazole inthe procedure of Example 1.A. (450 mg, white solid); MS (ESI): m/z 236[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 7.70-7.74 (d, J=9.6, 1H), 7.58-7.60(d, J=9.6, 1H), 7.25-7.39 (m, 1H), 5.64-5.67 (dd, J₁=8.8 Hz, J₂=2.4 Hz,1H), 4.60-4.64 (m, 1H), 4.53-4.58 (m, 2H), 4.24-4.29 (m, 1H), 3.91-3.95(d, J=9.6, 1H), 3.59-3.65 (m, 1H), 2.85 (s, 3H).

Example 1.8. Preparation of1-(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanaminiumchloride (8)

Compound 8 was prepared using a procedure analogous to that describedfor compound 3 but using compound 7 in place of compound 1 in theprocedure of Example 1.F. (240 mg, white solid); MS (ESI): m/z 250[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 7.70-7.74 (d, J=9.6, 1H), 7.63-7.66(d, J=9.6, 1H), 7.30-7.36 (m, 1H), 5.82-5.85 (dd, J=10.4, 2.8 Hz, 1H),4.62-4.68 (m, 1H), 4.55-4.60 (m, 2H), 4.27-4.33 (m, 1H), 4.06-4.10 (d,J=13.6, 1H), 3.70-3.76 (m, 1H), 3.15 (s, 3H), 3.04 (s, 3H).

Example 1.9. Preparation of(9-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanaminiumchloride (9)

Compound 9 was prepared a procedure analogous to that described forcompound 1 but using intermediate I-20 in place of intermediate I-7 inthe procedure of Example 1.1. (60 mg, white solid); MS (ESI): m/z 222[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 7.70-7.73 (d, J=9.2, 1H), 7.49-7.52(d, J=9.6, 1H), 7.27-7.32 (m, 1H), 5.55-5.58 (dd, J=7.8, 2.8 Hz, 1H),4.59-4.62 (m, 1H), 4.52-4.56 (m, 2H), 4.22-4.28 (m, 1H), 3.79-3.83 (d,J=13.6 Hz, 1H), 3.51-3.57 (m, 1H).

Example 1.10. Preparation of1-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylmethanaminium(10)

Compound 10 was prepared using a procedure analogous to that describedfor compound 5 but using 6-fluoro-1H-indazole in place of 1H-indazole inthe procedure of Example 1.A. (450 mg, white solid); MS (ESI): m/z 236[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 8.07-8.03 (m, 1H), 7.41-7.38 (dd,J=9.6, 2.4 Hz, 1H), 7.20-7.15 (m, 1H), 5.76 (d, J=1.6 Hz, 1H), 4.65 (m,1H), 4.57 (d, J=9.2 Hz, 2H), 4.29 (t, J=8.8 Hz, 1H), 4.01 (m, 1H), 3.67(m, 1H), 3.33 (m, 1H), 2.86 (s, 3H).

Example 1.11. Preparation of1-(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylmethanaminium(11)

Compound 11 was prepared using a procedure analogous to that describedfor compound 3 but using compound 10 in place of compound 1 in theprocedure of Example 1.F. (240 mg, white solid); MS (ESI): m/z 250[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 8.07-8.10 (m, 1H), 7.39-7.36 (dd,J=9.6, 2.4 Hz, 1H), 7.20-7.15 (m, 1H), 5.92 (d, J=2.4 Hz, 1H), 4.68 (m,1H), 4.57-4.62 (m, 2H), 4.32 (m, 1H), 4.18-4.14 (d, J=3.2, 1H),3.83-3.77 (m, 1H), 3.18 (s, 3H), 3.07 (s, 1H).

Example 1.12. Preparation of(8-fluoro-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanaminium(12)

Compound 12 was prepared using a procedure analogous to that describedfor compound 9 but using 6-fluoro-1H-indazole in place of 1H-indazole inthe procedure of Example 1.A. (60 mg, white solid); MS (ESI): m/z 222[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 8.04-8.01 (m, 1H), 7.41-7.38 (dd,J=9.6, 2.4 Hz, 1H), 7.19-7.15 (m, 1H), 5.71 (d, J=6.0 Hz 1H), 4.68-4.57(m, 3H), 4.29 (m, 1H), 3.89 (d, J=7.2 Hz, 1H), 3.63 (m, 1H).

Example 1.13. Preparation of1-((S)-pyrrolidin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazolehydrochloride (13)

Compound 13 was prepared using a procedure analogous to that describedfor compound 5 but using (S)-tert-butyl2-formylpyrrolidine-1-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B. (80 mg,yellow oil); MS (ESI): m/z 244 [M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ7.89-7.91 (d, J=8.4, 1H), 7.69-7.71 (d, J=8.8, 1H), 7.47-7.51 (m, 1H),7.26-7.29 (m, 1H), 5.62 (s, 1H), 4.71-4.74 (m, 2H), 4.54-4.62 (m, 2H),4.24-4.28 (m, 1H), 3.28-3.32 (m, 2H), 2.41-2.45 (m, 2H), 2.08-2.26 (m,2H).

Example 1.14. Preparation of1-((S)-1-methylpyrrolidin-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazolehydrochloride (14)

Compound 14 was prepared using a procedure analogous to that describedfor compound 3 but using compound 13 in place of compound 1 in theprocedure of Example 1.F. (60 mg, yellow oil); MS (ESI): m/z 258 [M+H]⁺;¹H NMR (400 MHz, MeOD): δ 7.70-7.72 (d, J=8.4 Hz, 1H), 7.58-7.60 (d,J=8.8 Hz, 1H), 7.31-7.35 (m, 1H), 7.08-7.12 (m, 1H), 5.44 (s, 1H),4.42-4.61 (m, 3H), 4.08-4.15 (m, 1H), 3.33-3.35 (m, 1H), 3.14-3.16 (m,1H), 2.59 (s, 3H), 2.40-2.44 (m, 1H), 1.68-1.76 (m, 3H), 1.49-1.54 (m,1H).

Example 1.15. Preparation of(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanamine (15)

Compound 15 was prepared using a procedure analogous to that describedfor intermediate I-19 but using 1H-indazole in the procedure of Example1.A (as shown, in place of the 5-fluoro-1H-indazole used in Example 1.L.(4.2 g, white solid); MS (ESI): m/z 204 [M+H]⁺; ¹H NMR (400 MHz, MeOD):δ 7.65 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.32 (t, J=7.2 Hz,1H), 7.08 (t, J=7.2 Hz, 1H), 5.18 (d, J=6.8 Hz, 1H), 4.52-4.49 (m, 1H),4.45-4.38 (m, 2H), 4.13-4.10 (m, 1H), 3.40 (dd, J=14.0, 2.0 Hz, 1H),3.21-3.15 (m, 1H).

Example 1.16. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)cyclobutanamine (16)

Compound 16 was prepared using a procedure analogous to that describedfor intermediate I-8 but using compound 15 in place of compound 1 andcyclobutanone in place of paraformaldehyde in the procedure of Example1.F. (67 mg, white solid); MS (ESI): m/z 258 [M+H]⁺; ¹H-NMR (400 MHz,MeOD): δ 7.66 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.33 (t, J=7.2Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 5.31 (d, J=7.2 Hz, 1H), 4.54 (m, 1H),4.44 (m, 2H), 4.13 (m, 1H), 3.38-3.30 (m, 2H), 3.12-3.10 (m, 1H),2.25-2.21 (m, 2H), 1.87-1.70 (m, 4H).

Example 1.17. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)propan-2-amine(17)

Compound 17 was prepared using a procedure analogous to that describedfor intermediate I-8 but using compound 15 in place of compound 1 andpropan-2-one in place of paraformaldehyde in the procedure of Example1.F. (97 mg, white solid); MS (ESI): m/z 246 [M+H]⁺; ¹H NMR (400 MHz,MeOD): δ 7.67 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.33 (t, J=6.8Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 5.35 (dd, J=8.4, 2.8 Hz, 1H), 4.54-4.51(m, 1H), 4.48-4.41 (m, 2H), 4.17-4.11 (m, 1H), 3.43 (dd, J=12.8, 3.2 Hz,1H), 3.15 (dd, J=12.8, 8.4 Hz, 1H), 2.98-2.95 (m, 1H), 1.14 (t, J=5.6Hz, 6H).

Example 1.18. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl) ethanaminehydrogen chloride salt (18)

Compound 18 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-22 in place of intermediate I-7in the procedure of Example 1.1. (92 mg, white solid); MS (ESI): m/z 232[M+H]⁺; ¹H-NMR (400 MHz, MeOD): δ 7.68 (d, J=8.4 Hz, 1H), 7.59 (d, J=8.8Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 5.36 (dd,J=8.8, 2.8 Hz, 1H), 4.54-4.50 (m, 1H), 4.48-4.41 (m, 2H), 4.16-4.11 (m,1H), 3.42 (dd, J=12.8, 3.2 Hz, 1H), 3.16 (dd, J=12.8, 8.4 Hz, 1H),2.79-2.75 (m, 2H), 1.17 (t, J=7.2 Hz, 3H).

Example 1.19. Preparation of1-(pyrrolidin-1-ylmethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazolehydrogen chloride salt (19)

Compound 19 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-26 in place of intermediate I-7in the procedure of Example 1.1. (white solid); MS (ESI): m/z 258[M+H]⁺; 1H NMR (400 MHz, d⁴-methanol): δ 8.01 (d, J=8.7 Hz, 1H), 7.72(d, J=8.7 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H),5.82-5.94 (m, 1H), 4.66-4.78 (m, 1H), 4.55-4.66 (m, 2H), 4.27-4.40 (m,1H), 4.14-4.25 (m, 1H), 3.84-3.99 (m, 2H), 3.67-3.81 (m, 1H), 3.39-3.54(m, 1H), 3.22-3.31 (m, 1H), 1.96-2.38 (m, 4H).

Example 1.20. Preparation of1-(morpholinomethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole hydrogenchloride salt (20)

Compound 20 was prepared using a procedure analogous to that describedfor compound 19 but using morpholine in place of pyrrolidine in theprocedure of Example 1.U. (White solid); MS (ESI): m/z 274 [M+H]⁺; 1HNMR (400 MHz, d⁴-methanol): δ 8.01 (d, J=8.5 Hz, 1H), 7.72 (d, J=8.7 Hz,1H), 7.60 (t, J=7.7 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 5.99-6.07 (m, 1H),4.57-4.66 (m, 1H), 4.66-4.76 (m, 2H), 4.26-4.38 (m, 1H), 4.05-4.21 (m,3H), 3.90-4.03 (m, 2H), 3.76-3.88 (m, 2H), 3.60-3.70 (m, 1H), 3.38-3.56(m, 2H).

Example 1.21. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)cyclopropanamine hydrogen chloride salt (21)

Compound 21 was prepared using a procedure analogous to that describedfor compound 19 but using cyclopropylamine in place of pyrrolidine inthe procedure of Example 1.U. (White solid); MS (ESI): m/z 244 [M+H]⁺;1H NMR (400 MHz, d⁴-methanol): δ 7.85-8.10 (m, 1H), 7.46-7.79 (m, 2H),7.24-7.44 (m, 1H), 5.69-5.89 (m, 1H), 4.50-4.77 (m, 3H), 4.22-4.37 (m,1H), 4.03-4.15 (m, 1H), 3.74-3.89 (m, 1H), 2.86-2.99 (m, 1H), 0.84-1.14(m, 4H).

Example 1.22. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylcyclopropanaminehydrogen chloride salt (22)

Compound 22 was prepared using a procedure analogous to that describedfor compound 3 but using compound 21 in place of compound 1 in theprocedure of Example 1.F. (50.0 mg); MS (ESI): m/z 258 [M+H]⁺; 1H-NMR(400 MHz, d⁴-methanol): δ 8.10-8.20 (m, 1H), 7.69-7.79 (m, 2H),7.42-7.47 (m, 1H), 5.95-6.25 (m, 1H), 4.57-4.80 (m, 3H), 4.30-4.40 (m,2H), 3.89-4.14 (m, 1H), 3.10-3.30 (m, 4H), 1.16-1.46 (m, 2H), 0.94-1.14(m, 2H).

Example 1.23.Preparation of1′-methyl-3,4-dihydrospiro[[1,4]oxazino[4,3-b]indazole-1,3′-pyrrolidin]-1′-iumchloride (23)

Compound 23 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-27 in place of compound 1 in theprocedure of Example 1.F. (160 mg, white solid, 95%); MS (ESI): m/z 244[M+H]⁺; 1H-NMR (400 MHz, CDCl₃): δ 7.69 (dd, J=19.6, 8.6 Hz, 2H), 7.29(dd, J=13.5, 5.6 Hz, 1H), 7.11-7.01 (m, 1H), 4.47 (t, J=5.0 Hz, 2H),4.23-4.15 (m, 2H), 3.12-2.98 (m, 3H), 2.83 (dd, J=14.8, 8.6 Hz, 1H),2.59-2.50 (m, 1H), 2.49 (s, 3H), 2.45-2.35 (m, 1H).

Example 1.24. Preparation of1′-methyl-3,4-dihydrospiro[[1,4]oxazino[4,3-b]indazole-1,4′-piperidin]-1′-iumchloride (24)

Compound 24 was prepared using a procedure analogous to that describedfor compound 23 but using tert-butyl 4-oxopiperidine-1-carboxylate inplace of tert-butyl methyl(2-oxoethyl)carbamate in the procedure ofExample 1.I. (160 mg, white solid); MS (ESI): m/z 258 [M+H]⁺; 1H-NMR(400 MHz, CDCl₃): δ 7.75 (d, J=8.5 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H),7.31-7.24 (m, 1H), 7.04 (ddd, J=8.4, 6.7, 0.7 Hz, 1H), 4.51-4.41 (m,2H), 4.23-4.11 (m, 2H), 2.79 (dd, J=6.8, 5.4 Hz, 2H), 2.51-2.40 (m, 4H),2.38 (s, 3H), 2.07-1.94 (m, 2H).

Example 1.25. Preparation of(2R)-2-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorpholin-4-iumchloride (25)

Compound 25 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-29 in place of intermediate I-7in the procedure of Example 1.1. (160 mg, white solid); MS (ESI): m/z274 [M+H]⁺; 1H-NMR (400 MHz, CDCl₃): δ 7.69 (dd, J=12.1, 8.6 Hz, 2H),7.32-7.24 (m, 1H), 7.04 (dd, J=7.9, 7.2 Hz, 1H), 5.17 (s, 1H), 4.55(ddd, J=13.4, 9.3, 4.1 Hz, 1H), 4.50-4.35 (m, 2H), 4.24 (dt, J=10.4, 2.2Hz, 1H), 4.06-3.94 (m, 1H), 3.88 (dd, J=11.5, 2.3 Hz, 1H), 3.64 (td,J=11.5, 2.4 Hz, 1H), 2.82 (d, J=11.2 Hz, 1H), 2.63 (d, J=11.6 Hz, 1H),2.29 (s, 3H), 2.21 (t, J=10.9 Hz, 1H), 2.17-2.06 (m, 1H).

Example 1.26. Preparation of(2R)-2-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorpholin-4-iumchloride (26)

Compound 26 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-30 in place of intermediate I-7in the procedure of Example 1.1. (160 mg, white solid); MS (ESI): m/z274 [M+H]⁺; 1H-NMR (400 MHz, CDCl₃): δ 7.74-7.63 (m, 2H), 7.35-7.26 (m,1H), 7.09-7.02 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.61-4.49 (m, 1H),4.49-4.39 (m, 2H), 4.26 (ddd, J=10.3, 4.5, 2.3 Hz, 1H), 4.10-3.97 (m,2H), 3.81 (td, J=11.5, 2.5 Hz, 1H), 2.67 (d, J=11.7 Hz, 1H), 2.58-2.48(m, 1H), 2.22 (s, 3H), 2.21-2.14 (m, 2H).

Example 1.27. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylpropan-2-aminiumchloride (27)

Compound 27 was prepared using a procedure analogous to that describedfor compound 3 but using compound 17 in place of compound 1 in theprocedure of Example 1.F. (95 mg, white solid); MS (ESI): m/z 260[M+H]⁺; 1H-NMR (400 MHz, MeOD): δ 8.16 (dd, J=28.7, 8.5 Hz, 1H),7.83-7.70 (m, 2H), 7.51-7.43 (m, 1H), 6.20-6.01 (m, 1H), 4.89-4.74 (m,1H), 4.76-4.59 (m, 2H), 4.39 (ddd, J=12.5, 8.6, 3.7 Hz, 1H), 4.15-3.75(m, 3H), 3.17 (s, 2H), 2.95 (s, 1H), 1.47 (ddd, J=23.4, 12.7, 6.7 Hz,6H).

Example 1.28. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylethanaminiumchloride (28)

Compound 28 was prepared using a procedure analogous to that describedfor compound 3 but using compound 18 in place of compound 1 in theprocedure of Example 1.F. (130 mg, white solid); MS (ESI): m/z 246[M+H]⁺; ¹H NMR (400 MHz, MeOD): δ 8.17-8.01 (m, 1H), 7.82-7.63 (m, 2H),7.49-7.36 (m, 1H), 6.03 (s, 1H), 4.84-4.72 (m, 1H), 4.72-4.57 (m, 2H),4.42-4.30 (m, 1H), 4.14 (m, 1H), 3.87 (m, 1H), 3.53 (m, 2H), 3.11 (dd,J=55.7, 1.5 Hz, 3H), 1.46 (dt, J=33.4, 7.3 Hz, 3H).

Example 1.29. Preparation ofN-((3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylcyclobutanaminiumchloride (29)

Compound 29 was prepared using a procedure analogous to that describedfor compound 3 but using compound 16 in place of compound 1 in theprocedure of Example 1.F. (130 mg, white solid); MS (ESI): m/z 272[M+H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (d, J=8.7 Hz, 1H), 7.61 (d,J=8.5 Hz, 1H), 7.32-7.27 (m, 1H), 7.11-7.03 (m, 1H), 5.34 (d, J=8.1 Hz,1H), 4.62-4.50 (m, 1H), 4.50-4.38 (m, 2H), 4.12-4.00 (m, 1H), 2.96 (m,2H), 2.81 (dd, J=13.7, 9.2 Hz, 1H), 2.37 (s, 3H), 2.09-1.91 (m, 3H),1.77-1.58 (m, 3H).

Example 1.30. Preparation of(+/−)-rel-(R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethanaminium chloride (30)

Compound 30 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-32 in place of intermediate I-8in the procedure of Example 1.3. (55.0 mg, white solid); MS (ESI): m/z218 [M+H]⁺; 1H NMR (400 MHz, d⁴-methanol): δ 7.80 (d, J=8.4 Hz, 1H),7.70 (d, J=9.1 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H),5.58-5.63 (m, 1H), 4.51-4.75 (m, 3H), 4.36-4.46 (m, 1H), 4.18-4.29 (m,1H), 1.12 (d, J=6.9 Hz, 3H).

Example 1.31. Preparation of(+/−)-rel-(R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylethanaminiumchloride (31)

Compound 31 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-34 in place of intermediate I-8in the procedure of Example 1.3. (300 mg, white solid); MS (ESI): m/z232 [M+H]⁺; 1H-NMR (400 MHz, d⁴-methanol): δ 7.79 (d, J=8.6 Hz, 1H),7.68 (d, J=8.7 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H),5.67-5.76 (m, 1H), 4.48-4.72 (m, 3H), 4.17-4.34 (m, 2H), 2.93 (s, 3H),1.12 (d, J=6.8 Hz, 3H).

Example 1.32. Preparation of(+/−)-rel-(R)-1-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N,N-dimethylethanaminiumchloride (32)

Compound 32 was prepared using a procedure analogous to that describedfor compound 3 but using compound 31 in place of compound 1 in theprocedure of Example 1.F. (150 mg, white solid); MS (ESI): m/z 246[M+H]⁺; 1H-NMR (400 MHz, d⁴-methanol): δ 7.98 (d, J=8.6 Hz, 1H), 7.74(d, J=8.7 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H),6.00-6.10 (m, 1H), 4.68-4.80 (m, 1H), 4.55-4.67 (m, 2H), 4.35-4.45 (m,1H), 4.28 (td, J=11.7, 3.5 Hz, 1H), 3.20 (s, 3H), 3.13 (s, 3H), 1.23 (d,J=6.8 Hz, 3H).

Example 1.33. Preparation of(+/−)-rel-(R)-1-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethanaminium chloride (33)

Compound 33 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-33 in place of intermediate I-7in the procedure of Example 1.1. (100 mg, white solid); MS (ESI): m/z218 [M+H]⁺; 1H-NMR (400 MHz, d⁴-methanol): δ 7.93 (d, J=8.6 Hz, 1H),7.74 (d, J=8.7 Hz, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H),5.52-5.56 (m, 1H), 4.53-4.73 (m, 3H), 4.32-4.41 (m, 1H), 4.18-4.28 (m,1H), 1.67 (d, J=6.7 Hz, 3H).

Example 1.34. Preparation of(+/−)-rel-(R)-1-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-N-methylethanaminiumchloride (34)

Compound 34 was prepared using a procedure analogous to that describedfor compound 31 but using intermediate I-33 in place of intermediateI-32 in the procedure of Example 1.Y. (110 mg, white solid); MS (ESI):m/z 232 [M+H]⁺; 1H-NMR (400 MHz, d⁴-Methanol): δ 7.95-8.12 (m, 1H),7.59-7.86 (m, 2H), 7.35-7.54 (m, 1H), 5.57-5.73 (m, 1H), 4.56-4.86 (m,3H), 4.21-4.42 (m, 2H), 2.62 (s, 3H), 1.72 (dd, J=6.9, 2.6 Hz, 3H).

Example 1.35. Preparation of4-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)piperidin-1-iumchloride (35)

Compound 35 was prepared using a procedure analogous to that describedfor intermediate I-4 but using tert-butyl4-formylpiperidine-1-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B, followed byhydrochlorination using a procedure analogous to that described inExample 1.3. (293 mg, white solid); MS (ESI): m/z 258.1 [M+H]⁺; ¹H NMR(400 MHz, MeOH-d₄): □ 8.16 (d, 1H), 7.83-7.78 (m, 2H), 5.44 (s, 1H),4.77-4.74 (m, 1H), 4.64-4.55 (m, 2H), 4.23-4.17 (m, 1H), 3.56 (d, 1H),3.31-3.39 (m, 1H), 3.19-3.29 (m, 1H), 3.01-2.94 (m, 2H), 2.22-2.17 (m,2H), 1.86-1.81 (m, 1H), 1.37 (d, 1H).

Example 1.36. Preparation of3′,4′-dihydrospiro[piperidine-4,1′-[1,4]oxazino[4,3-b]indazol]-1-iumchloride (36)

Compound 36 was prepared using a procedure analogous to that describedfor intermediate I-4 but using tert-butyl 4-oxopiperidine-1-carboxylatein place of tert-butyl methyl(2-oxoethyl)carbamate in the procedure ofExample 1.B, followed by hydrochlorination using a procedure analogousto that described in Example 1.3. (175 mg, white solid); MS (ESI): m/z244.2 [M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄): □ 8.20 (d, 1H), 7.77-7.72 (m,2H), 7.46 (t, 1H), 4.66 (br, 2H), 4.42 (br, 2H), 3.51 (br, 4H), 2.79(br, 2H), 2.43 (d, 2H).

Example 1.37. Preparation of3′,4′-dihydro-4-azaspiro[bicyclo[2.2.1]heptane-2,1′-[1,4]oxazino[4,3-b]indazol]-4-iumchloride (37)

Compound 37 was prepared using a procedure analogous to that describedfor intermediate I-4 but using 1-azabicyclo[2.2.1]heptan-3-one in placeof tert-butyl methyl(2-oxoethyl)carbamate in the procedure of Example1.B, followed by hydrochlorination using a procedure analogous to thatdescribed in Example 1.3. (240 mg, white solid); MS (ESI): m/z 256.2[M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄); □ 7.81-7.79 (m, 1H), 7.74-7.72 (m,1H), 7.56-7.52 (m, 1H), 7.38-7.33 (m, 1H), 4.65-4.57 (m, 3H), 4.46-4.39(m, 1H), 4.13 (dd, 1H), 3.96-3.89 (m, 2H), 3.80-3.70 (m, 3H), 3.50 (dd,1H), 2.36-2.27 (m, 1H), 2.13-2.06 (m, 1H).

Example 1.38. Preparation of (3S)-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)piperidin-1-ium(38)

Compound 38 was prepared using a procedure analogous to that describedfor intermediate I-4 but using (S)-tert-butyl3-formylpiperidine-1-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B, followed byhydrochlorination using a procedure analogous to that described inExample 1.3. (120 mg, pale-brown solid); MS (ESI): m/z 258.0 [M+H]⁺; ¹HNMR (400 MHz, MeOH-d₄) □ 8.03-7.96 (m, 1H), 7.77-7.66 (m, 2H), 7.44-7.39(m, 1H), 5.48-5.44 (m, 1H), 4.74-4.66 (m, 1H), 4.58-4.53 (m, 2H),4.21-4.13 (m, 1H), 3.69-3.68 (m, 0.4H), 3.41-3.30 (m, 1.6H), 3.06-2.88(m, 3H), 2.17-1.89 (m, 2.6H), 1.76-1.61 (m, 0.8H), 1.38-1.29 (m, 0.6H).

Example 1.39. Preparation of(1-methyl-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methanaminiumchloride (39)

Compound 39 was prepared using a procedure analogous to that describedfor intermediate I-4 but using tert-butyl (2-oxopropyl)carbamate inplace of tert-butyl methyl(2-oxoethyl)carbamate in the procedure ofExample 1.B, followed by hydrochlorination using a procedure analogousto that described in Example 1.3. (80 mg, pale-brown solid); MS (ESI):m/z 218.1 [M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄) □ 8.06 (d, 1H), 7.80-7.71(m, 2H), 7.48-7.43 (m, 1H), 4.76-4.69 (m, 1H), 4.66-4.60 (m, 1H),4.51-4.40 (m, 2H), 3.86 (d, 1H), 3.67-3.65 (m, 1H), 1.92 (s, 3H).

Example 1.40. Preparation of3′,4′-dihydrospiro[azetidine-3,1′-[1,4]oxazino[4,3-b]indazol]-1-iumchloride (40)

To a solution of intermediate I-36 (440 mg, 1.07 mmol) intetrahydrofuran (20 mL) was added potassium tert-butoxide (0.36 g, 3.21mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs and quenchedwith 10 ml of water. The crude reaction mixture was extracted with ethylacetate (3×30 mL), the combined organic phase was dried over sodiumsulfate and solids were removed by filtration. The filtrate wasconcentrated in vacuo and purified by preparative TLC (ethylacetate:petrol ether=2:1) to give a white foamy solid. To the solid wasadded 5 ml of HCl-Methanol (3 N) and the reaction mixture was stirred atroom temperature for 4 hrs and concentrated in vacuo to give compound40. (92 mg, 35%, pale-brown solid); MS (ESI): m/z 216.1 [M+H]⁺; ¹H NMR(400 MHz, MeOH-d₄) □ 7.86-7.85 (m, 1H), 7.59-7.58 (m, 1H), 7.40-7.35 (m,1H), 7.22-7.17 (m, 1H), 4.79-4.78 (m, 2H), 4.40-4.38 (m, 2H), 4.33-4.32(m, 2H), 4.25-4.23 (m, 2H).

Example 1.41. Preparation of(1R)-2-cyclobutyl-1-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)ethan-1-aminium(41)

Compound 41 was prepared using a procedure analogous to that describedfor intermediate I-4 but using (R)-tert-butyl(1-cyclobutyl-3-oxopropan-2-yl)carbamate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B, followed byhydrochlorination using a procedure analogous to that described inExample 1.3. (97 mg, pale-brown solid); MS (ESI): m/z 272.1 [M+H]⁺; ¹HNMR (400 MHz, MeOH-d₄) □ 7.90-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.65-7.63(m, 1H), 7.39-7.34 (m, 1H), 5.69 & 5.60 (s & s, 1H), 4.78-4.57 (m, 3H),4.26-4.06 (m, 2H), 2.71-2.65 (m, 0.5H), 2.33-2.19 (m, 2H), 2.09-1.76 (m,4.5H), 1.68-1.48 (m, 1H), 1.38-1.25 (m, 1H).

Example 1.42. Preparation of(2R)-2-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-4-iumchloride (42)

Compound 42 was prepared using a procedure analogous to that describedfor intermediate I-4 but using (R)-tert-butyl2-formylmorpholine-4-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B, followed byhydrochlorination using a procedure analogous to that described inExample 1.3. (41 mg, pale-white solid); MS (ESI): m/z 260.0 [M+H]⁺; ¹HNMR (400 MHz, MeOH-d₄) □ 8.05-8.03 (m, 1H), 7.74-7.61 (m, 2H), 7.44-7.32(m, 1H), 5.65-5.47 (m, 1H), 4.77-4.46 (m, 4H), 4.30-4.21 (m, 1.4H),4.04-3.90 (m, 1H), 3.85-3.78 (m, 0.6H), 3.66-3.64 (m, 0.6H), 3.49-3.13(m, 3.4H).

Example 1.43. Preparation (3S)-3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-4-iumchloride (43)

Compound 43 was prepared using a procedure analogous to that describedfor intermediate I-4 but using (S)-tert-butyl3-formylmorpholine-4-carboxylate in place of tert-butylmethyl(2-oxoethyl)carbamate in the procedure of Example 1.B, followed byhydrochlorination using a procedure analogous to that described inExample 1.3. (75 mg, pale-white solid); MS (ESI): m/z 260.1 [M+H]⁺; ¹HNMR (400 MHz, MeOH-d₄) □ 7.95-7.94 (m, 1H), 7.73-7.72 (m, 1H), 7.56-7.55(m, 1H), 7.34-7.33 (m, 1H), 4.71-4.50 (m, 4H), 4.27-4.20 (m, 1H),4.06-4.04 (m, 1H), 3.81-3.72 (m, 2H), 3.61-3.43 (m, 3H).

Example 1.44. Preparation of3′,4′-dihydrospiro[pyrrolidine-3,1′-[1,4]oxazino[4,3-b]indazol]-1-iumchloride (44)

Compound 44 was prepared using a procedure analogous to that describedfor intermediate I-4 but using tert-butyl 3-oxopyrrolidine-1-carboxylatein place of tert-butyl methyl(2-oxoethyl)carbamate in the procedure ofExample 1.B, followed by hydrochlorination using a procedure analogousto that described in Example 1.3. (90 mg, pale-yellow solid); MS (ESI):m/z 229.9 [M+H]⁺; ¹H NMR (400 MHz, MeOH-d₄) □ 8.08-8.07 (m, 1H),7.75-7.74 (m, 1H), 7.65-7.63 (m, 1H), 7.40-7.38 (m, 1H), 4.66-4.65 (m,2H), 4.46-4.45 (m, 2H), 3.89-3.65 (m, 4H), 2.80-2.79 (m, 2H).

Example 1.45. Preparation of(+/−)-(S)-3-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-4-iumchloride (45)

Compound 45 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-39 in place of intermediate I-7in the procedure of Example 1.1. (0.19 g); MS (ESI): m/z 260 [M+H]⁺;¹H-NMR (400 MHz, MeOD-d4) δ 7.66-7.60 (m, 2H), 7.29-7.25 (m, 1H),7.07-7.03 (m, 1H), 5.15-5.14 (d, J=3.6 Hz, 1H), 4.48-4.35 (m, 3H),3.95-3.94 (m, 1H), 3.77-3.73 (m, 1H), 3.66-3.64 (m, 1H), 3.50-3.49 (m,1H), 3.44-3.38 (m, 2H), 3.06-2.99 (m, 2H).

Example 1.46. Preparation of(+/−)-(S)-3-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)morpholin-4-iumchloride (46)

Compound 46 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-40 in place of intermediate I-7in the procedure of Example 1.1. (0.12 g); MS (ESI): m/z 260 [M+H]⁺;¹H-NMR (400 MHz, MeOD-d4) δ 7.70-7.60 (m, 2H), 7.31-7.29 (m, 1H),7.11-7.09 (m, 1H), 5.13-5.12 (d, J=3.6 Hz, 1H), 4.65-4.55 (m, 1H),4.48-4.38 (m, 2H), 4.01-3.98 (m, 2H), 3.86-3.78 (m, 2H), 3.68-3.64 (m,1H), 3.58-3.52 (m, 1H), 2.96-2.84 (m, 2H).

Example 1.47. Preparation of (+/−)-(3S,4R)-3-((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorpholin-4-iumchloride (47)

Compound 47 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-39 in place of compound 1 in theprocedure of Example 1.F. (0.08 g); MS (ESI): m/z 274 [M+H]⁺; ¹H NMR(400 MHz, MeOD-d4) δ 7.71-7.68 (d, J=8.8 Hz, 1H), 7.64-7.62 (d, J=8.8Hz, 1H), 7.34-7.30 (m, 1H), 7.12-7.10 (d, J=8.8 Hz, 1H), 5.62 (d, J=2.4Hz, 1H), 4.52-4.45 (m, 3H), 4.02-3.94 (m, 1H), 3.79-3.78 (m, 1H),3.70-3.69 (m, 1H), 3.60-3.54 (m, 1H), 3.35-3.34 (m, 1H), 3.02-3.00 (m,1H), 2.89-2.86 (m, 1H), 2.60 (s, 3H), 2.55-2.54 (m, 1H).

Example 1.48. Preparation of (+/−)-(3S,4R)-3-((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-4-methylmorpholin-4-iumchloride (48)

Compound 48 was prepared using a procedure analogous to that describedfor compound 3 but using intermediate I-40 in place of compound 1 in theprocedure of Example 1.F. (0.11 g); MS (ESI): m/z 274 [M+H]⁺; ¹H-NMR(400 MHz, MeOD-d4) δ 7.98-7.95 (d, J=8.4 Hz, 1H), 7.66-7.63 (d, J=8.4Hz, 1H), 7.29-7.27 (m, 1H), 7.07-7.05 (m, 1H), 5.21 (s, 1H), 4.56-4.39(m, 3H), 3.96-3.95 (m, 1H), 3.90-3.87 (m, 1H), 3.78-3.76 (m, 1H),3.61-3.60 (m, 1H), 3.52-3.47 (m, 1H), 2.99-2.97 (m, 1H), 2.76-2.74 (m,1H), 2.45-2.44 (m, 1H), 2.13 (s, 3H).

Example 1.49. Preparation ofN—(((S)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylethanaminiumchloride (49)

Compound 49 was prepared using a procedure analogous to that describedfor compound 3 but using acetaldehyde in place of paraformaldehyde inthe procedure of Example 1.F. (1.5 g, Yield 88%); MS (ESI): m/z 246[M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4) δ 8.13-8.08 (m, 1H), 7.78-7.76 (m,1H), 7.74-7.68 (m, 1H), 7.45-7.42 (m, 1H), 6.05-6.03 (m, 1H), 4.80-4.74(m, 1H), 4.69-4.61 (m, 2H), 4.40-4.33 (m, 1H), 4.21-4.17 (m, 1H),4.11-4.08 (m, 1H), 3.93-3.86 (m, 1H), 3.69-3.64 (m, 0.41H), 3.55-3.36(m, 1.57H), 3.18 (s, 1.77H), 3.04 (s, 1.21H), 1.50 (t, J=7.3 Hz, 1.24H),1.42 (t, J=7.3 Hz, 1.76H).

Example 1.50. Preparation ofN—(((R)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)methyl)-N-methylethanaminiumchloride (50)

Compound 50 was prepared using a procedure analogous to that describedfor compound 4 but using acetaldehyde in place of paraformaldehyde inthe procedure of Example 1.F. (1.4 g); MS (ESI): m/z 246 [M+H]⁺; ¹H NMR(400 MHz, MeOD-d4) δ 8.12-8.07 (m, 1H), 7.78-7.77 (m, 1H), 7.76-7.69 (m,1H), 7.46-7.42 (m, 1H), 6.04-6.00 (m, 1H), 4.80-4.73 (m, 1H), 4.69-4.61(m, 2H), 4.40-4.33 (m, 1H), 4.21-4.09 (m, 1H), 4.11-4.07 (m, 1H),3.93-3.80 (m, 1H), 3.67-3.64 (m, 0.41H), 3.49-3.36 (m, 1.63H), 3.18 (s,1.78H), 3.04 (s, 1.19H), 1.50 (t, J=7.3 Hz, 1.23H), 1.42 (t, J=7.3 Hz,1.77H).

Example 1.51. Preparation of1-(4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)-N-methylmethanaminiumchloride (51)

Compound 51 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-46 in place of intermediate I-7in the procedure of Example 1.1. (60 mg, white solid); MS (ESI): m/z 232[M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4) δ 7.98 (d, J=8.4 Hz, 1H), 7.71 (d,J=8.4 Hz, 1H), 7.63 (t, J=8.4 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 5.70 (d,J=10.0 Hz, 1H), 5.00-4.98 (m, 2H), 4.48-4.43 (m, 1H), 4.22-4.00 (m, 3H),2.96 (s, 3H), 2.27 (br-s, 2H).

Example 1.52. Preparation of1-(4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)-N,N-dimethylmethanaminiumchloride (52)

Compound 52 was prepared using a procedure analogous to that describedfor compound 3 but using compound 51 in place of compound 1 in theprocedure of Example 1.F. (128 mg, white solid); MS (ESI): m/z 246[M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4) δ 8.05 (d, J=8.7 Hz, 1H), 7.79-7.67(m, 2H), 7.51-7.40 (m, 1H), 6.01-5.83 (m, 1H), 5.05 (s, 2H), 4.47 (dt,J=12.4, 4.6 Hz, 1H), 4.33-4.19 (m, 3H), 3.18 (d, J=5.7 Hz, 6H),2.36-2.22 (m, 2H).

Example 1.53. PreparationN-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)-N-methylethanaminiumchloride (53)

Compound 53 was prepared using a procedure analogous to that describedfor compound 52 but using acetaldehyde in place of paraformaldehyde inthe procedure of Example 1.F. (118 mg, white solid); MS (ESI): m/z 260[M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4) δ 7.65 (d, J=8.8 Hz, 1H), 7.58 (d,J=8.8 Hz, 1H), 7.24 (t, J=8.8 Hz, 1H), 7.06-7.02 (m, 1H), 5.20-5.17 (m,1H), 4.92-4.89 (m, 1H), 4.73-4.65 (m, 1H), 4.35-4.30 (m, 1H), 3.82-3.78(m, 1H), 3.27-3.21 (m, 1H), 3.07-3.03 (m, 1H), 2.68-2.59 (m, 2H), 2.42(s, 3H), 2.17-1.85 (m, 2H), 1.11 (t, J=7.2 Hz, 3H).

Example 1.54. Preparation ofN-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)-N-methylpropan-2-aminiumchloride (54)

Compound 54 was prepared using a procedure analogous to that describedfor compound 52 but using acetone in place of paraformaldehyde in theprocedure of Example 1.F. (142 mg, white solid); MS (ESI): m/z 274[M+H]⁺; ¹H-NMR (400 MHz, CDCl₃) δ 7.59-7.50 (m, 1H), 7.51-7.43 (m, 1H),7.18-7.07 (m, 1H), 7.01-6.87 (m, 1H), 5.05 (dd, J=5.5, 3.4 Hz, 1H),4.87-4.71 (m, 1H), 4.61-4.46 (m, 1H), 4.24-4.13 (m, 1H), 3.66 (dd,J=13.5, 9.1 Hz, 1H), 3.13-2.99 (m, 1H), 2.94 (d, J=13.5 Hz, 1H),2.89-2.76 (m, 1H), 2.29 (d, J=2.9 Hz, 3H), 1.94 (dd, J=41.8, 2.9 Hz,2H), 0.92 (ddd, J=9.5, 6.6, 2.8 Hz, 6H).

Example 1.55. Preparation ofN-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)-N-methylcyclobutanaminiumchloride (55)

Compound 55 was prepared using a procedure analogous to that describedfor compound 52 but using cyclobutanone in place of paraformaldehyde inthe procedure of Example 1.F. (99 mg, white solid); MS (ESI): m/z 286[M+H]⁺; ¹H-NMR (400 MHz, D₂O) δ 7.56 (dd, J=18.2, 8.7 Hz, 2H), 7.33 (dd,J=8.2, 7.4 Hz, 1H), 7.16-7.09 (m, 1H), 5.49 (dd, J=11.1, 2.9 Hz, 1H),4.76-4.72 (m, 2H), 4.33 (dt, J=12.5, 3.8 Hz, 1H), 4.14-3.83 (m, 4H),2.88 (d, J=10.5 Hz, 3H), 2.48-2.12 (m, 4H), 2.00 (dd, J=18.7, 4.1 Hz,2H), 1.77 (dd, J=18.2, 10.2 Hz, 2H).

Example 1.56. Preparation of(4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methanaminiumchloride (56)

Compound 56 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-51 in place of intermediate I-7in the procedure of Example 1.1. (89 mg, white solid); MS (ESI): m/z 218[M+H]⁺. ¹H-NMR (400 MHz, MeOD-d4) δ 7.76 (d, J=8.7 Hz, 1H), 7.67 (d,J=8.8 Hz, 1H), 7.51-7.41 (m, 1H), 7.29-7.20 (m, 1H), 5.38 (dd, J=10.8,3.0 Hz, 1H), 4.91-4.79 (m, 2H), 4.43 (s, 1H), 4.14-3.98 (m, 2H), 3.84(s, 1H), 2.26-2.10 (m, 2H).

Example 1.57. Preparation ofN-((4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-b]indazol-1-yl)methyl)ethanaminiumchloride (57)

Compound 57 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-52 in place of intermediate I-7in the procedure of Example 1.1. (72 mg, white solid) as white solid; MS(ESI): m/z 246 [M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4) δ 7.90 (d, J=8.7 Hz,1H), 7.70 (d, J=8.8 Hz, 1H), 7.59-7.51 (m, 1H), 7.34 (dd, J=8.1, 7.0 Hz,1H), 5.58 (dd, J=10.8, 2.8 Hz, 1H), 4.92 (s, 2H), 4.55-4.37 (m, 1H),4.22-4.04 (m, 2H), 4.01 (d, J=11.2 Hz, 1H), 3.33-3.27 (m, 2H), 2.24 (dd,J=10.5, 5.8 Hz, 2H), 1.46 (t, J=7.3 Hz, 3H).

Example 1.58. Preparation of1-(6,7-dihydro-9H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-methylmethanaminiumchloride (58)

Compound 58 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-58 in place of intermediate I-7in the procedure of Example 1.1. (53 mg, white solid); MS (ESI): m/z 224[M+H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (d, J=5.2 Hz, 1H), 7.12 (d,J=5.2 Hz, 1H), 5.44-5.42 (m, 1H), 4.54-4.38 (m, 3H), 4.27-4.21 (m, 1H),3.74-3.70 (m, 1H), 3.54-3.49 (m, 1H), 2.82 (s, 3H).

Example 1.59. Preparation of1-(6,7-dihydro-9H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N,N-dimethylmethanaminiumchloride (59)

Compound 59 was prepared using a procedure analogous to that describedfor compound 3 but using compound 58 in place of compound 1 in theprocedure of Example 1.F. (56 mg, white solid); MS (ESI): m/z 238[M+H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 7.31 (d, J=5.5 Hz, 1H), 7.05 (d,J=5.5 Hz, 1H), 4.98 (t, J=6.8 Hz, 1H), 4.48-4.34 (m, 2H), 4.33-4.26 (m,1H), 4.07 (td, J=11.4, 3.5 Hz, 1H), 2.79 (qd, J=12.5, 6.8 Hz, 2H), 2.40(s, 6H).

Example 1.60. Synthesis of(6,7-dihydro-9H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)methanaminiumchloride (60)

Compound 60 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-63 in place of intermediate I-7in the procedure of Example 1.1. (56 mg, white solid); MS (ESI): m/z 210[M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4): δ 7.63 (d, J=5.3 Hz, 1H), 7.13 (d,J=5.4 Hz, 1H), 5.38 (dd, J=7.7, 2.8 Hz, 1H), 4.57-4.45 (m, 2H),4.44-4.36 (m, 1H), 4.29-4.19 (m, 1H), 3.65 (dd, J=13.4, 2.7 Hz, 1H),3.42 (dd, J=13.5, 7.8 Hz, 1H).

Example 1.61. Synthesis of1-((methylammonio)methyl)-3,4-dihydro-1H-pyrido[3′,4′:3,4]pyrazolo[5,1-c][1,4]oxazin-8-iumchloride (61)

Compound 61 was prepared using a procedure analogous to that describedfor compound 1 but using intermediate I-68 in place of intermediate I-7in the procedure of Example 1.1. (55.4 mg, yellow solid); MS (ESI): m/z219 [M+H]⁺; ¹H-NMR (400 MHz, MeOD-d4): δ 9.79 (s, 1H), 8.54 (d, J=6.8Hz, 1H), 8.28 (d, J=6.8 Hz, 1H), 5.82-5.79 (m, 1H), 4.86-4.84 (m, 2H),4.67-4.63 (m, 1H), 4.39-4.35 (m, 1H), 4.07-4.03 (m, 1H), 3.71-3.68 (m,1H), 2.89 (s, 3H).

Example 1.62. Synthesis of1-((dimethylammonio)methyl)-3,4-dihydro-1H-pyrido[3′,4′:3,4]pyrazolo[5,1-c][1,4]oxazin-8-iumchloride (62)

Compound 62 was prepared using a procedure analogous to that asdescribed for compound 3 but using compound 61 in place of compound 1 inthe procedure of Example 1.F. (60 mg, yellow solid); MS (ESI): m/z 233[M+H]⁺, ¹H-NMR (400 MHz, MeOD-d4): δ 9.79 (s, 1H), 8.58 (d, J=6.8 Hz,1H), 8.28 (d, J=6.8 Hz, 1H), 5.98-5.94 (m, 1H), 5.45-5.42 (m, 1H),4.68-4.65 (m, 1H), 4.58-4.55 (m, 1H), 4.44-4.38 (m, 2H), 4.30-4.22 (m,2H), 4.19-4.13 (m, 1H), 3.07 (s, 3H), 3.02 (s, 3H).

Example 1.63. Preparation of1-(aziridin-1-ylmethyl)-3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazole (63)

To a solution of compound 15 (0.34 g, 1.67 mmol) in a mixture ofdichloroethane/acetonitrile (4 mL/2 mL) was added solid K₃PO₄ (354 mg,1.67 μmol) in a sealed tube. The reaction mixture was stirred at 130° C.for 3 hrs. The crude reaction mixture was filtered, the filtrate wasconcentrated in vacuo and the residue was purified by silica gelchromatography. Compound 63 was obtained as yellow oil (90 mg, 20%, MS(ESI): m/z 230 [M+H]⁺. ¹H-NMR (500 MHz CDCl₃): δ 7.68 (d, J=8.8 Hz, 1H),7.55 (d, J=8.5 Hz, 1H), 7.36-7.26 (m, 1H), 7.13-7.00 (m, 1H), 5.55-5.32(m, 1H), 4.61-4.56 (m, 1H), 4.51-4.47 (m, 2H), 4.18-4.05 (m, 1H),3.11-3.08 (m, 1H), 2.76-2.72 (m, 1H), 1.89-1.87 (m, 2H), 1.36-1.30 (m,2H).

Example 1.64. Preparation of(2S)-2-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)azetidin-1-iumchloride (64)

Compound 64 was prepared using a procedure analogous to that describedfor compound 40 but using intermediate I-71 in place of intermediateI-36 in the procedure of Example 1.40. (129 mg as white solid). MS(ESI): m/z 230 [M+H]⁺. 1H-NMR (500 MHz, DMSO-d6): δ 7.78 (d, J=8.5 Hz,1H), 7.62 (d, J=8.5 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 7.08 (t, J=8.5 Hz,1H), 5.52 (s, 1H), 5.33 (br-s, 1H), 4.74-4.69 (m, 1H), 4.54-4.51 (m,1H), 4.44-4.42 (m, 1H), 4.21-4.16 (m, 1H), 3.88-3.85 (m, 1H), 3.75-3.72(m, 1H), 2.79-2.76 (m, 1H), 2.57-2.54 (m, 1H).

Example 1.65. Preparation of((2S)-2-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-1-methylazetidin-1-iumchloride (65)

Compound 65 was prepared using a procedure analogous to that describedfor compound 3 but using compound 64 in place of compound 1 in theprocedure of Example 1.F. (49.8 mg, as colorless oil). MS (ESI): m/z 244[M+H]⁺. 1H-NMR (500 MHz, CD₃OD): & 7.79 (d, J=8.4 Hz, 1H), 7.67 (d,J=8.4 Hz, 1H), 7.40 (t, J=8.5 Hz, 1H), 7.22 (t, J=8.5 Hz, 1H), 5.57 (s,1H), 5.43-5.41 (m, 1H), 4.74-4.65 (m, 2H), 4.54-4.51 (m, 1H), 4.33-4.26(m, 1H), 4.19-4.14 (m, 1H), 3.99-3.92 (m, 1H), 3.03-2.97 (m, 1H),2.74-2.70 (m, 1H), 2.49 (s, 3H).

Example 1.66. Preparation of3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)azetidin-1-iumchloride (66)

Compound 66 was prepared using a procedure analogous to that describedfor compound 3, but using tert-butyl 3-formylazetidine-1-carboxylate inplace of tert-butyl methyl(2-oxoethyl)carbamate in the procedure ofExample 1.B. MS (ESI): m/z 230 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD): & 7.80(m, 1H), 7.68 (m, 1H), 7.52 (m, 1H), 7.26 (m, 1H), 5.47 (brs, 1H),4.71-4.68 (m, 3H), 4.40-4.30 (m, 3H), 4.05-3.87 (m, 3H).

Example 1.67. Preparation of3-(3,4-dihydro-1H-[1,4]oxazino[4,3-b]indazol-1-yl)-1-methylazetidin-1-iumchloride (67)

Compound 67 was prepared using a procedure analogous to that describedfor compound 3, but using compound 66 in place of compound 1 in theprocedure of Example 1.F. MS (ESI): m/z 244 [M+H]+. 1H NMR (400 MHz,CD₃OD): δ 7.87-7.80 (m, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.58-7.54 (m, 1H),7.33-7.28 (m, 1H), 5.55 (s, 1H), 4.81-4.58 (m, 4H), 4.35-4.29 (m, 2H),4.13-3.98 (m, 3H), 2.92 (s, 3H).

Example 1.68. Preparation of(S)-1-(6,7-dihydro-9H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-methylmethanamine(68) and(R)-1-(6,7-dihydro-9H-thieno[3′,2′:3,4]pyrazolo[5,1-c][1,4]oxazin-9-yl)-N-methylmethanamine(69)

Compound 58 (4.0 g, 17.9 mmol) was separated into its enantiomers 68 and69 by chiral HPLC using column IC 20*250 mm, 5 μm (Daicel) and mobilephase CO₂/MeOH (0.2% NH₄OH)=65/35. The flow rate was 80 g/min, backpressure was 100 Bar and cycle time of stack injections was 5.3 min.Compound 68 (2.0 g, 50%, retention time 2.74 min) was obtained ascolorless oil. MS (ESI): m/z 224 [M+H]⁺. ¹H-NMR (500 MHz, CD₃OD): δ 7.85(d, J=5.0 Hz, 1H), 7.21 (d, J=5.0 Hz, 1H), 5.57-5.55 (m, 1H), 4.58-4.48(m, 3H), 4.32-4.27 (m, 1H), 3.80-3.77 (m, 1H), 3.59-3.55 (m, 1H), 2.84(s, 3H). Compound 69 (2.0 g, 50%, retention time 4.46 min) was obtainedas white solid. MS (ESI): m/z 224 [M+H]⁺. ¹H-NMR (500 MHz, CD₃OD): δ7.63 (d, J=5.0 Hz, 1H), 7.12 (d, J=5.0 Hz, 1H), 5.47-5.45 (m, 1H),4.54-4.39 (m, 3H), 4.27-4.22 (m, 1H), 3.75-3.72 (m, 1H), 3.54-3.50 (m,1H), 2.83 (s, 3H).

Example 2. Biological Assays Example 2.1. Tail Suspension Test

The tail suspension test (TST) is a rodent screening test for potential(human) antidepressant drugs. It is based on the assumption that ananimal will actively try to escape an aversive (stressful) stimulus. Ifescape is impossible, the animal will eventually stop trying (“giveup”). In the TST, a mouse is suspended by the tail so that its bodydangles in the air, head downward. Mice initially struggle to faceupward and climb to a solid surface. When the animal stops strugglingand hangs immobile it is considered to have “given up”. Shorter periodsof immobility are characteristic of anti-depressant-like activity.Accordingly, longer periods of immobility are considered indicative of adepressive-like state. It has been shown that treatment with anantidepressant drug will decrease the time the animal spends immobile.See generally L. Steru et al., Psychopharmacology (Berl). 1985;85(3):367-70; B. Thierry et al., Psychopharmacology 1986; 90:284-85.

Procedure.

Adult male CD 1 mice (Charles River Laboratories) receive either vehicle(sterile water or saline, 10 mL/kg) or compound (30 mg/kg) by ipinjection 30 min before being subjected to the Tail Suspension Test. Inthis test animals are suspended by the tail for 10 min during which thetime spent immobile is measured.

Mean Total Time Standard Error of p value (compound Compound Immobile(sec) the Mean vs vehicle) 2 76.6 25.9 <0.0001 4 74.9 13.0 <0.0001 6175.2 35.1 0.020 7 132.9 20.7 0.0012 8 237.5 30.0 0.12 9 189.4 18.80.0078 22 374.0 27.8 0.73 27 144.2 34.5 0.0002 28 98.0 33.9 <0.0001 29115.0 25.1 <0.0001 50 84.5 18.9 0.0005 61 162.0 26.6 <0.0001 68 86.130.6 <0.0001

Example 2.2. Neuropharmacological Assay (SmartCube™)

In order to further demonstrate the utility of the provided compounds totreat neurological and psychiatric diseases and disorders, exemplarycompounds were evaluated using the neuropharmacological screen describedin S. L. Roberds et al., Front. Neurosci. 2011 Sep. 9; 5:103 (doi:10.3389/fnins.2011.00103) (“Roberds”). As reported in Roberds, becausepsychiatric diseases generally result from disorders of cell-cellcommunication or circuitry, intact systems are useful in detectingimprovement in disease-relevant endpoints. These endpoints are typicallybehavioral in nature, often requiring human observation andinterpretation. To facilitate testing of multiple compounds forbehavioral effects relevant to psychiatric disease, PsychoGenics, Inc.(Tarrytown, N.Y., “PGI”) developed SmartCube™, an automated system inwhich behaviors of compound-treated mice are captured by digital videoand analyzed with computer algorithms. (D. Brunner et al., Drug Discov.Today 2002, 7:S107-S112). PGI Analytical Systems uses data fromSmartCube™ to compare the behavioral signature of a test compound to adatabase of behavioral signatures obtained using a large set of diversereference compounds. (The composition of the database as well asvalidation of the method is further described in Roberds). In this way,the neuropharmacological effects of a test compound can be predicted bysimilarity to major classes of compounds, such as antipsychotics,anxiolytics and antidepressants.

The SmartCube™ system produces an activity signature indicating theprobability that the activity of the test compound at the administereddose matches a given class of neuropharmacological agents. (See, e.g.,Roberds, FIGS. 2 and 3). The test compound is simultaneously comparedagainst multiple classes of agents; thus, a separate probability isgenerated for each behavioral effect measured (e.g., anxiolyticactivity, analgesic activity, etc.). In Table 2 and 2B, theseprobabilities are reported for each behavioral effect measured asfollows:

LOQ≤ + <5%  5%≤ ++ <25% 25%≤ +++ <50% 50%≤ ++++where LOQ is the limit of quantification.

Provided compounds were dissolved in a mixture of Pharmasolve™(N-methyl-2-pyrrolidone), polyethylene glycol and propylene glycol, andwere injected i.p. 15 min. before the behavioral test. For eachcompound, injections were administered at 3 different doses. For eachbehavioral effect measured, results for the most efficacious dose(s) arepresented.

TABLE 2 Compound DP AX SD PS MS AD CE AG XG HA UN 1 +++ + + + + + + + + + 2 ++++ ++ + + + ++ + + + ++++ + 3 ++ + +++ + + + + + + +++ 4 ++++ + + + + ++ ++ ++ + ++ ++ 5 ++ + + + + + +++ + + + 6 +++ ++ + ++ + + ++ ++ + + + 7 ++++ + + + + + + ++ + + + 8 +++++ + ++ + + ++ ++ ++ + + 9 ++ + + + + ++ ++ ++ + + +++ 10 ++++ ++ +++ + + + ++ ++ + + 11 +++ + ++ ++ + + + + + + + 12 + + + + + + + + + + +13 ++ ++ + + ++ + ++ +++ + + + 14 ++ +++ + ++ + + ++ + + + + 15++ + + + + ++++ + ++ + + + 16 + + + + + + + + + + + 17 ++++ + + + + + + + + ++ 18 + ++ + ++ + + ++ ++ + + + 19 +++ ++ + + + + ++++ + + + 20 ++ +++ + ++ + + ++ ++ + + + 21 ++ ++ + ++ + + + ++ + + + 22++++ ++ + + + ++ + + + ++ ++ 23 ++ ++++ + + + + ++ ++ + + + 24 ++ ++ +++ + + ++ ++ + + + 25 ++ ++ + + + ++ + ++ + + + 26 ++ + + + + + +++ + + + 27 ++++ + + + + + + ++ + + + 28 ++++ ++ + + + + ++ + + ++ ++ 29+++ ++ + + + + ++ + + ++ + 30 ++ +++ + + + ++ + ++ + ++ + 31 ++ +++ +++ + + ++ ++ + + +++ 32 ++ ++ + +++ + + ++ + + + ++ 33 ++ ++ + + +++++ + ++ + ++ +++ 34 + ++ + + + + + + + + + 35 + + + + + + + + + + + 36+++ ++ ++ ++ + + ++ ++ + + ++ 37 ++ ++ ++ ++ + + ++ ++ + + +++ 38 + ++ +++ ++ + + ++ + + + 39 ++ ++ + + + + + + + + + 40 ++ +++ ++ ++ + + ++++ + + + 41 + + + + + + + + + + + 42 + + + + + + + + + + +43 + + + + + + + + + + + 44 ++ +++ + ++ + + ++ ++ + + +45 + + + + + + + + + + + 46 + ++ ++ ++ + + + ++ + + ++ 47 + ++ + + + + +++ + + + 48 + + + + + + + + + + + 49 ++ ++ ++ + + + ++ +++ + + + 50 +++++++ + + + ++ + + + ++ + 51 +++ ++ + + + ++ + + + + + 52 ++++ + + + + + + + + ++ 53 ++ ++ ++ + + + + + + + ++ 54 +++ + + + + + + + + + 55 + ++ + + + + + + + + +++56 + + + + + + + + + + + 57 + + + + + + + + + + + 58 ++++ ++ ++ + +++ + + + ++ + 59 ++ ++ + ++ + + ++ ++ + + +++ 60 ++ +++ ++ + +++ + + + + + 61 ++++ + + + + ++ + + + ++ ++ 62 + ++ + + + + + + + + +I-4 ++++ +++ ++ + + ++ + + + ++ + 63 ++ + ++ + + + + +++ + + + 64 ++++ + + + ++++ + ++ + + +++ 65 ++ ++ ++ + + + ++ +++ ++ + + 66 ++++ + + + + + ++ + + + 67 ++ ++ + + + + + + + + + 68 ++++ ++ ++ + + ++ +++ + ++++ ++ 69 ++ ++ + + + + + + + + ++ DP: anti-depressant; AX:anxiolytic; SD: sedative hypnotic; PS: anti-psychotic; MS: moodstabilizer; AD: ADHD; CE: cognitive enhancer; AG: analgesic; XG:anxiogenic; HA: hallucinogen; UN: uncharacterized CNS activity

Some embodiments of the present invention are enumerated below. In suchpresentations, an embodiment reciting a “compound” with reference toanother enumerated embodiment either that itself explicitly recites “ora pharmaceutically acceptable salt thereof” or that refers ultimately toan enumerated embodiment that does, is intended to encompass both freecompounds and pharmaceutically acceptable salts thereof. As aconvention, the phrase “or a pharmaceutically acceptable salt thereof”is explicitly recited when the structural formula of the compound isexplicitly recited, but no difference in inclusion or exclusion ofpharmaceutically acceptable salts is thereby intended. For example, bothembodiments 1 and 2 are intended to encompass both the free compoundsand pharmaceutically acceptable salts thereof.

What is claimed is: 1-55. (canceled)
 56. A process for preparing acompound of formula

or a salt thereof, comprising: combining

and di-tert-butyl dicarbonate to form

resolving

into its enantiomers

and isolating

and deprotecting

to obtain

or a salt thereof.
 57. A process according to claim 56, wherein saidresolving is accomplished by chiral HPLC.
 58. A process according toclaim 56, further comprising combining

with 4-methylbenzenesulfonic acid to obtain


59. A process according to claim 58, further comprising combining

with lithium diisopropylamide to form a mixture, then combining themixture with tert-butyl methyl(2-oxoethyl)carbamate to obtain


60. A process according to claim 59, further comprising combining

in 2-bromoethanol to obtain


61. A process for preparing a compound of formula

or a salt thereof, comprising: a) combining

in 2-bromoethanol to obtain

b) combining

with lithium diisopropylamide to form a mixture, then combining themixture with tert-butyl methyl(2-oxoethyl)carbamate to obtain

c) combining

with 4-methylbenzenesulfonic acid to obtain

d) combining

and di-tert-butyl dicarbonate to form

e) resolving

into its enantiomers

and isolating

and f) deprotecting

to obtain

or a salt thereof.
 62. A process according to claim 61, wherein saidresolving in step e) is accomplished by chiral HPLC.
 63. A process forresolving a compound of formula

into its enantiomers, comprising: a) combining

and di-tert-butyl dicarbonate to form

b) resolving

into its enantiomers

and c) deprotecting with acid to obtain


64. The process according to claim 63, further comprising isolating


65. A process according to claim 63, further comprising combining

with 4-methylbenzenesulfonic acid to obtain


66. A process according to claim 65, further comprising combining

with lithium diisopropylamide to form a mixture, then combining themixture with tert-butyl methyl(2-oxoethyl)carbamate to obtain


67. A process according to claim 66, further comprising combining

in 2-bromoethanol to obtain


68. A compound selected from:

or a pharmaceutically acceptable salt thereof.